Compounds and methods for treating cancer

ABSTRACT

The present application relates to compounds comprising an ester, a thioester, or a hydrazide moiety and methods of synthesizing these compounds. The present application also relates to pharmaceutical compositions containing the compounds and methods of treating cell proliferative disorders mediated by the Hh signaling pathway, such as cancer, by administering the compounds and pharmaceutical compositions to subjects in need thereof.

RELATED APPLICATIONS

This application is a divisional application of U.S. application Ser.No. 15/577,845, now allowed, which is a U.S. National Phase application,filed under 35 U.S.C. § 371, of International Application No.PCT/US2016/035641, filed on Jun. 3, 2016, which claims priority to, andthe benefit of U.S. Provisional Application No. 62/171,783, filed onJun. 5, 2015, the contents of each of which are incorporated herein byreference in their entireties.

BACKGROUND

Aberrant regulation of the Hedgehog (Hh) signaling pathway drivesseveral cancers, including medulloblastoma (MB) and Basal Cell Carcinoma(BCC), and is often caused by mutations to Patched (PTCH) or Smoothened(SMO) (Amakye et al., Nat. Med. 19, 1410 (2013)). Loss of functionmutations to PTCH in the germline are responsible for Gorlin syndrome(also known as nevoid basal cell carcinoma syndrome, NBCCS), a seriousgenetic disorder that predisposes an individual to several forms ofcancer, including MB and BCC (Gorlin, Genet. Med. 6, 530 (2004)).Fortunately, SMO has proved extensively receptive to regulation by smallmolecules (Sharpe et al., Nat. Chem. Biol. 11, 246 (2015)).

SMO is a GPCR-like molecule whose activity can be modulated by varioussmall molecules, including several currently under clinicalinvestigation for Hedgehog-related pathologies. Although SMO transducesthe Hedgehog signal across the cell membrane, Hedgehog ligands actuallybind and inactivate the transporter like molecule PTCH, which functionsas a tumor suppressor and represses the activity of SMO. Vismodegib, aSMO antagonist, has been approved for the treatment of locally advancedand metastatic BCC since 2012 (Hoff et al., New Eng. J. Med. 361, 1164(2009), Sharpe et al., 2015). However, in a Phase II study of vismodegibin patients with NBCCS, over half (14 of 26) of the participants ceasedtreatment due to serious adverse effects (Tang et al., New Eng. J. Med.366, 2180 (2012)). Accordingly, new compounds and methods for treatingproliferation disorders mediated by the Hh signaling pathway, includingcancer, are needed. The present application addresses these needs.

In order to increase the therapeutic index of SMO antagonism as atreatment for BCC, retrometabolic (soft) drug design is employed in thedevelopment of novel SMO antagonists. In retrometabolic drug design,metabolic reaction information is used to design drugs whose metabolismand distribution can be controlled to target and eliminate the drug toincrease efficacy and minimize undesirable side effects. Theseapproaches represent systematic methodologies that thoroughly integratestructure-activity (SAR) and structure-metabolism (SMR) relationshipsand are aimed at designing safe, locally active compounds with improvedtherapeutic index (ratio of benefit vs. side effect). For example,inclusion of ester functionality into the compounds creates SMOantagonists with a liability to serum esterases, which enables rapidmetabolic inactivation of the drug in the bloodstream. Also, topicaltreatment with such compounds will provide high therapeuticconcentrations local to the site of application while avoiding systemiceffects.

SUMMARY

The present application provides compounds comprising an ester moiety(i.e., C(O)O), a thioester moiety (i.e., C(O)S), or a hydrazide moiety(i.e., C(O)NH—NH), and methods for treating disorders mediated by the Hhsignaling pathway. Specifically, the present application provides acompound of formula A:

or a pharmaceutically acceptable salt thereof, wherein R₁, Z₁, Z₂, and nare each defined herein and can each be selected from the respectivegroups of chemical moieties disclosed herein in the detaileddescription.

The present application also provides pharmaceutical compositionscomprising one or more compounds of any of the formulae described hereinor a pharmaceutically acceptable salt thereof, and one or morepharmaceutically acceptable carriers.

The present application also provides topical compositions comprisingone or more compounds of any of the formulae described herein or apharmaceutically acceptable salt thereof, and one or morepharmaceutically acceptable carriers.

The present application also provides methods of modulating the SMO,comprising contacting the SMO with a compound of the any of the formulaedescribed herein or a pharmaceutically acceptable salt thereof.

The present application also provides methods of treating a disordermediated by the Hh signaling pathway, by administering to a subject inneed thereof, a therapeutically effective amount of a compound of any ofthe formulae described herein, or a pharmaceutically acceptable saltthereof, in combination with a pharmaceutically acceptable carrier, suchthat the disorder is treated.

The present application also provides methods of treating a cellproliferative disorder mediated by the Hh signaling pathway, byadministering to a subject in need thereof, a therapeutically effectiveamount of a compound of any of the formulae described herein, or apharmaceutically acceptable salt thereof, in combination with apharmaceutically acceptable carrier, such that the disorder is treated.

The present application also provides methods of treating cancermediated by the Hh signaling pathway, by administering to a subject inneed thereof, a therapeutically effective amount of a compound of any ofthe formulae described herein, or a pharmaceutically acceptable saltthereof, in combination with a pharmaceutically acceptable carrier, suchthat the cancer is treated.

The present application also relates to use of a compound of any of theformulae described herein, or a pharmaceutically acceptable salt thereoffor the treatment of a disorder, a cell proliferative disorder, or acancer mediated by the Hh signaling pathway.

The present application also relates to use of a compound of any of theformulae described herein, or a pharmaceutically acceptable saltthereof, in the manufacture of a medicament for the treatment of adisorder, a cell proliferative disorder, or a cancer mediated by the Hhsignaling pathway.

The present application provides methods of synthesizing compounds ofeach of the formulae described herein, or pharmaceutically acceptablesalts thereof.

Unless otherwise defined, all technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art to which this application belongs. In the specification, thesingular forms also include the plural unless the context clearlydictates otherwise. Although methods and materials similar or equivalentto those described herein can be used in the practice or testing of thepresent application, suitable methods and materials are described below.All publications, patent applications, patents, and other referencesmentioned herein are incorporated by reference. The references citedherein are not admitted to be prior art to the claimed application. Inthe case of conflict, the present specification, including definitions,will control. In addition, the materials, methods, and examples areillustrative only and are not intended to be limiting.

Other features and advantages of the application will be apparent fromthe following detailed description and claims.

DESCRIPTION OF THE DRAWINGS

FIG. 1: top panel: a graph showing the amount of the indicated compoundsincubated at 37° C. in serum-free media or serum over time; bottompanel: a graph showing the amount of vismoister incubated at 37° C. inserum-free media or serum over time.

FIG. 2: a graph showing the amount of erismoester incubated at 37° C. inserum over time.

FIG. 3: a graph showing the amount of LY-ester incubated at 37° C. inserum over time.

FIG. 4: a graph showing the number of viable mouse medulloblastoma cells(indicated as relative luminescence) 24 hours after treatment of thecells with increasing concentrations of the indicated compounds.

FIG. 5: a graph showing the number of viable mouse medulloblastoma cells(indicated as relative luminescence) 48 hours after treatment of thecells with increasing concentrations of the indicated compounds.

FIG. 6: a graph showing the number of viable mouse medulloblastoma cells(indicated as relative luminescence) 72 hours after treatment of thecells with increasing concentrations of the indicated compounds.

FIG. 7: a graph showing the number of viable mouse medulloblastoma cells(indicated as relative luminescence) 96 hours after treatment of thecells with increasing concentrations of the indicated compounds.

FIG. 8: graphs showing the expression of Hh target genes (Gli1 (leftpanel) and Ptch 1 (right panel)) in mouse medulloblastoma cells 24 hoursafter treatment of the cells with 1 μM of the indicated compounds.

FIG. 9: bar graphs showing the expression of Hh target genes in mousemedulloblastoma cells at various time points after treatment of thecells with 1 μM of the indicated compounds.

FIG. 10: bar graphs showing the expression of Hh target genes (indicatedas relative luciferase activity) in Shh-Light2 cells (NIH/3T3 cellsstably expressing Hh responsive firefly luciferase) 24 hours aftertreatment of the cells with the indicated compounds. Left panel: thecells were treated once with 20 nM Smoothened Agonist (SAG) or 10 μM ofthe indicated compounds. Right panel: the cells were treated twice (at 0hr and at 20 hr) with 20 nM Smoothened Agonist (SAG) or 10 μM of theindicated compounds.

DETAILED DESCRIPTION

1. Compounds of the Present Application

The present application provides compounds or pharmaceuticallyacceptable salts thereof, pharmaceutical compositions (e.g., topicalformulations) containing them, and various uses of the disclosedcompounds and pharmaceutically acceptable salts thereof. The compoundsof the present application are inhibitors of SMO in the Hh signalingpathway, and is able to inhibit or decrease the activity of SMO. Ingeneral, the compounds of the present application comprises an estermoiety (i.e., C(O)O), a thioester moiety (i.e., C(O)S), or a hydrazidemoiety (i.e., C(O)NH—NH). In some embodiments, compounds of the presentapplication comprise an ester moiety, a thioester moiety, or a hydrazidemoiety in the place of an amide moiety in compounds which can inhibit ordecrease the activity of SMO. For example, the compounds of the presentapplication have the following structure:

each having an ester moiety, as compared to the amide moiety in thecompounds below:

The compounds of the present application display various desirableproperties.

In one embodiment, the compounds of the present application (e.g.,vismoester, erismoester, or LY-ester) are metabolized in vivo at a ratethat is at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%,150%, or 200% faster than the metabolism rate of a compound that doesnot have the ester moiety, the thioester moiety, or the hydrazidemoiety. In one embodiment, the compound that does not have the estermoiety, the thioester moiety, or the hydrazide moiety is a compound thathas an amide moiety in the place of the ester moiety, the thioestermoiety, or the hydrazide moiety (e.g., vismodegib, erismodegib, orLY2040680).

In one embodiment, the compounds of the present application (e.g.,vismoester, erismoester, or LY-ester) can be degraded, for example, byan esterase in the serum. In one embodiment, the compounds of thepresent application can be degraded, for example, by a serum esterase,at a rate that is at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%,100%, 150%, or 200% faster than the rate of degradation of a compoundthat does not have the ester moiety, the thioester moiety, or thehydrazide moiety. In one embodiment, the compound that does not have theester moiety, the thioester moiety, or the hydrazide moiety is acompound that has an amide moiety in the place of the ester moiety, thethioester moiety, or the hydrazide moiety (e.g., vismodegib,erismodegib, or LY2040680).

In one embodiment, the compounds of the present application (e.g.,vismoester, erismoester, or LY-ester) can be degraded in serum (i.e.,serum from blood) with a T112 (i.e., the time when half of the compoundis degraded) less than 120 hours, less than 96 hours, less than 72hours, less than 48 hours, less than 36 hours, less than 24 hours, lessthan 12 hours, less than 8 hours, less than 4 hours, less than 2 hours,less than 1 hour, or less than 30 minutes.

In one embodiment, the compounds of the present application (e.g.,vismoester, erismoester, or LY-ester) have a therapeutic index (TI) thatis at least 1.1 fold, 1.2 fold, 1.3 fold, 1.4 fold, 1.5 fold, 2.0 fold,2.5 fold, 3.0 fold, 3.5 fold, 4.0 fold, 4.5 fold, 5 fold, 10 fold, 15fold, 20 fold, 30 fold, 40 fold, 50 fold, 70 fold, 100 fold, 150 fold,200 fold, or 500 fold higher than the TI of a compound that does nothave the ester moiety, the thioester moiety, or the hydrazide moiety. Inone embodiment, the compound that does not have the ester moiety, thethioester moiety, or the hydrazide moiety is a compound that has anamide moiety in the place of the ester moiety, the thioester moiety, orthe hydrazide moiety (e.g., vismodegib, erismodegib, or LY2040680).

In one embodiment, the compounds of the present application (e.g.,vismoester, erismoester, or LY-ester) have a LD₅₀ that is at least 1.1fold, 1.2 fold, 1.3 fold, 1.4 fold, 1.5 fold, 2.0 fold, 2.5 fold, 3.0fold, 3.5 fold, 4.0 fold, 4.5 fold, 5 fold, 10 fold, 15 fold, 20 fold,30 fold, 40 fold, 50 fold, 70 fold, 100 fold, 150 fold, 200 fold, or 500fold higher than the LD₅₀ of a compound that does not have the estermoiety, the thioester moiety, or the hydrazide moiety. In oneembodiment, the compound that does not have the ester moiety, thethioester moiety, or the hydrazide moiety is a compound that has anamide moiety in the place of the ester moiety, the thioester moiety, orthe hydrazide moiety (e.g., vismodegib, erismodegib, or LY2040680).

In one embodiment, the compounds of the present application (e.g.,vismoester, erismoester, or LY-ester) have a TD₅₀ that is at least 1.1fold, 1.2 fold, 1.3 fold, 1.4 fold, 1.5 fold, 2.0 fold, 2.5 fold, 3.0fold, 3.5 fold, 4.0 fold, 4.5 fold, 5 fold, 10 fold, 15 fold, 20 fold,30 fold, 40 fold, 50 fold, 70 fold, 100 fold, 150 fold, 200 fold, or 500fold higher than the TD₅₀ of a compound that does not have the estermoiety, the thioester moiety, or the hydrazide moiety. In oneembodiment, the compound that does not have the ester moiety, thethioester moiety, or the hydrazide moiety is a compound that has anamide moiety in the place of the ester moiety, the thioester moiety, orthe hydrazide moiety (e.g., vismodegib, erismodegib, or LY2040680).

In one embodiment, the compounds of the present application (e.g.,vismoester, erismoester, or LY-ester) have a plasma exposure is at least1.1 fold, 1.2 fold, 1.3 fold, 1.4 fold, 1.5 fold, 2.0 fold, 2.5 fold,3.0 fold, 3.5 fold, 4.0 fold, 4.5 fold, 5 fold, 10 fold, 15 fold, 20fold, 30 fold, 40 fold, 50 fold, 70 fold, 100 fold, 150 fold, 200 fold,or 500 fold less than the plasma exposure of a compound that does nothave the ester moiety, the thioester moiety, or the hydrazide moiety. Inone embodiment, the compound that does not have the ester moiety, thethioester moiety, or the hydrazide moiety is a compound that has anamide moiety in the place of the ester moiety, the thioester moiety, orthe hydrazide moiety (e.g., vismodegib, erismodegib, or LY2040680).

The present application provides a compound of formula A:

or a pharmaceutically acceptable salt thereof, wherein:

Z₁-Z₂ is C(O)—O, O—C(O), C(O)—S, S—C(O), C(O)—NR—NR, or NR—NR—C(O);

each R is independently H or C₁-C₃ alkyl;

n is 0, 1, 2, 3, 4, or 5;

each R₁ is independently halogen, OH, cyano, unsubstituted orsubstituted C₁-C₆ alkyl, unsubstituted or substituted C₁-C₆ alkoxy,C(O)-(unsubstituted or substituted C₁-C₆ alkyl), S(O)_(m)-(unsubstitutedor substituted C₁-C₆ alkyl), unsubstituted or substituted phenyl, NH₂,NH-heteroaryl, wherein the heteroaryl comprises one or two 5- to8-membered rings and 1-4 heteroatoms selected from O, N, and S and isoptionally substituted;

m is 0, 1, or 2; and

is unsubstituted or substituted phenyl, unsubstituted or substitutedheteroaryl comprising one 5- or 6-membered ring and 1-3 heteroatomsselected from N, O, and S, or unsubstituted or substituted heterocyclylcomprising one 5- or 6-membered ring and 1-3 heteroatoms selected fromN, O, and S.

In one embodiment, Z₁-Z₂ is C(O)—O, O—C(O), C(O)—S, or S—C(O).

In one embodiment, Z₁-Z₂ is C(O)—S, S—C(O), C(O)—NR—NR, or NR—NR—C(O).

In one embodiment, Z₁-Z₂ is C(O)—O or O—C(O).

In one embodiment, Z₁-Z₂ is C(O)—O.

In one embodiment, Z₁-Z₂ is C(O)—S or S—C(O).

In one embodiment, Z₁-Z₂ is C(O)—S.

In one embodiment, Z₁-Z₂ is C(O)—NR—NR or NR—NR—C(O).

In one embodiment, Z₁-Z₂ is C(O)—NR—NR.

In one embodiment, each R is H (i.e., Z₁-Z₂ is C(O)—NH—NH orNH—NH—C(O)).

In one embodiment, one of R is H, and the other R is C₁-C₃ alkyl (e.g.,methyl, ethyl, or propyl).

In one embodiment, each R is C₁-C₃ alkyl (e.g., methyl, ethyl, orpropyl).

In one embodiment, n is 0, 1, or 2.

In one embodiment, n is 0.

In one embodiment, n is 1.

In one embodiment, n is 2.

In one embodiment, n is 3.

In one embodiment, n is 4.

In one embodiment, n is 5.

In one embodiment, at least one R₁ is halogen (e.g., F, Cl, Br, or I).

In one embodiment, at least one R₁ is OH.

In one embodiment, at least one R₁ is cyano.

In one embodiment, at least one R₁ is NH₂.

In one embodiment, at least one R₁ is unsubstituted or substitutedstraight-chain C₁-C₆ alkyl or branched C₃-C₆ alkyl. In a furtherembodiment, at least one R₁ is methyl, ethyl, propyl, i-propyl, butyl,i-butyl, t-butyl, pentyl, or hexyl, each of which is optionallysubstituted with halogen (e.g., F, Cl, Br, or I).

In one embodiment, at least one R₁ is unsubstituted or substitutedstraight-chain C₁-C₆ alkoxy or branched C₃-C₆ alkoxy. In a furtherembodiment, at least one R₁ is methoxy, ethoxy, propoxy, i-propoxy,butoxy, i-butoxy, t-butoxy, pentoxy, or hexyloxy, each of which isoptionally substituted with halogen (e.g., F, Cl, Br, or I).

In one embodiment, at least one R₁ is C(O)-(unsubstituted or substitutedC₁-C₆ alkyl), wherein the unsubstituted or substituted C₁-C₆ alkyl isselected from methyl, ethyl, propyl, i-propyl, butyl, i-butyl, t-butyl,pentyl, and hexyl, each of which is optionally substituted with halogen(e.g., F, Cl, Br, or I).

In one embodiment, at least one R₁ is S(O)_(m)-(unsubstituted orsubstituted C₁-C₆ alkyl). In a further embodiment, at least one R₁ isS-(unsubstituted or substituted C₁-C₆ alkyl). In another furtherembodiment, at least one R₁ is S(O)-(unsubstituted or substituted C₁-C₆alkyl). In another further embodiment, at least one R₁ isS(O)₂-(unsubstituted or substituted C₁-C₆ alkyl). In a furtherembodiment, the unsubstituted or substituted C₁-C₆ alkyl is selectedfrom methyl, ethyl, propyl, i-propyl, butyl, i-butyl, t-butyl, pentyl,and hexyl, each of which is optionally substituted with halogen (e.g.,F, Cl, Br, or I).

In one embodiment, m is 0.

In one embodiment, m is 1.

In one embodiment, m is 2.

In one embodiment, at least one R₁ is phenyl optionally substituted withone or more substituents independently selected from halogen, cyano,unsubstituted or substituted C₁-C₆ alkyl, unsubstituted or substitutedC₁-C₆ alkoxy, S-(unsubstituted or substituted C₁-C₆ alkyl),S(O)-(unsubstituted or substituted C₁-C₆ alkyl), S(O)₂-(unsubstituted orsubstituted C₁-C₆ alkyl), amino, di-C₁-C₆ alkylamino, and unsubstitutedor substituted C₆-C₁₀ aryl.

In one embodiment, at least one R₁ is NH-heteroaryl. In a furtherembodiment, the heteroaryl is selected from pyrrolyl, pyrazolyl,imidazolyl, pyridinyl, pyrimidyl, indolyl, quinolinyl, and quinazolinyl,each of which is optionally substituted with one or more substituentsindependently selected from halogen, OH, unsubstituted or substitutedC₁-C₆ alkyl, unsubstituted or substituted C₁-C₆ alkoxy, andunsubstituted or substituted phenyl.

In one embodiment,

is unsubstituted phenyl or phenyl substituted with one or moresubstituents independently selected from halogen, OH, cyano,unsubstituted or substituted C₁-C₆ alkyl, unsubstituted or substitutedC₁-C₆ alkoxy, C(O)OH, C(O)-(unsubstituted or substituted C₁-C₆ alkyl),C(O)-(unsubstituted or substituted C₁-C₆ alkoxy), C(O)NH-(unsubstitutedor substituted C₁-C₆ alkyl), S-(unsubstituted or substituted C₁-C₆alkyl), S(O)-(unsubstituted or substituted C₁-C₆ alkyl),S(O)₂-(unsubstituted or substituted C₁-C₆ alkyl), (CH₂)₀₋₆—NH₂,(CH₂)₀₋₆—NH—C₁-C₆ alkyl, (CH₂)₀₋₆—N(C₁-C₆ alkyl)₂, unsubstituted orsubstituted C₃-C₈ cycloalkyl, unsubstituted or substituted C₆-C₁₀ aryl,unsubstituted or substituted heterocyclyl comprising one or two 5- to8-membered rings and 1-4 heteroatoms selected from 0, N, and S, andunsubstituted or substituted heteroaryl comprising one or two 5- to8-membered rings and 1-4 heteroatoms selected from O, N, and S.

In a further embodiment,

is unsubstituted phenyl or phenyl substituted with one or moresubstituents independently selected from halogen, OH, cyano,unsubstituted or substituted C₁-C₆ alkyl, unsubstituted or substitutedC₁-C₆ alkoxy, C(O)OH, C(O)-(unsubstituted or substituted C₁-C₆ alkyl),C(O)-(unsubstituted or substituted C₁-C₆ alkoxy), C(O)NH-(unsubstitutedor substituted C₁-C₆ alkyl), S-(unsubstituted or substituted C₁-C₆alkyl), S(O)-(unsubstituted or substituted C₁-C₆ alkyl),S(O)₂-(unsubstituted or substituted C₁-C₆ alkyl), (CH₂)₀₋₆—NH₂,(CH₂)₀₋₆—NH—C₁-C₆ alkyl, and (CH₂)₀₋₆—N(C₁-C₆ alkyl)₂. In a furtherembodiment,

is phenyl substituted with one or more substituents independentlyselected from halogen, OH, unsubstituted or substituted C₁-C₆ alkyl,unsubstituted or substituted C₁-C₆ alkoxy, C(O)OH, C(O)-(unsubstitutedor substituted C₁-C₆ alkyl), (CH₂)₀₋₆—NH₂, (CH₂)₀₋₆—NH—C₁-C₆ alkyl, and(CH₂)₀₋₆—N(C₁-C₆ alkyl)₂.

In a further embodiment,

is unsubstituted phenyl or phenyl substituted with one or moresubstituents independently selected from unsubstituted or substitutedC₃-C₈ cycloalkyl, unsubstituted or substituted C₆-C₁₀ aryl,unsubstituted or substituted heterocyclyl comprising one or two 5- to8-membered rings and 1-4 heteroatoms selected from O, N, and S, andunsubstituted or substituted heteroaryl comprising one or two 5- to8-membered rings and 1-4 heteroatoms selected from O, N, and S. In afurther embodiment,

is phenyl substituted with heteroaryl selected from pyridinyl,pyrimidinyl, indolyl, imidazopyridinyl.

In one embodiment,

is unsubstituted heteroaryl or heteroaryl substituted with one or moresubstituents independently selected from halogen, OH, cyano,unsubstituted or substituted C₁-C₆ alkyl, unsubstituted or substitutedC₁-C₆ alkoxy, C(O)OH, C(O)-(unsubstituted or substituted C₁-C₆ alkyl),C(O)-(unsubstituted or substituted C₁-C₆ alkoxy), C(O)NH-(unsubstitutedor substituted C₁-C₆ alkyl), S-(unsubstituted or substituted C₁-C₆alkyl), S(O)-(unsubstituted or substituted C₁-C₆ alkyl),S(O)₂-(unsubstituted or substituted C₁-C₆ alkyl), unsubstituted orsubstituted C₃-C₈ cycloalkyl, unsubstituted or substituted C₆-C₁₀ aryl,unsubstituted or substituted heterocyclyl comprising one or two 5- to8-membered rings and 1-4 heteroatoms selected from O, N, and S,unsubstituted or substituted heteroaryl comprising one or two 5- to8-membered rings and 1-4 heteroatoms selected from O, N, and S, S(O)₂R₂,C(O)R₂, OR₂, and NR₃R₄, wherein:

-   -   R₂ is unsubstituted or substituted C₃-C₈ cycloalkyl,        unsubstituted or substituted C₆-C₁₀ aryl, unsubstituted or        substituted heterocyclyl comprising one or two 5- to 8-membered        rings and 1-4 heteroatoms selected from O, N, and S, or        unsubstituted or substituted heteroaryl comprising one or two 5-        to 8-membered rings and 1-4 heteroatoms selected from O, N, and        S; and    -   R₃ and R₄ are each independently H or unsubstituted or        substituted C₁-C₆ alkyl.        In a further embodiment,

is heteroaryl substituted with one or more substituents independentlyselected from halogen, OH, cyano, unsubstituted or substituted C₁-C₆alkyl, unsubstituted or substituted C₁-C₆ alkoxy, unsubstituted orsubstituted C₃-C₈ cycloalkyl, unsubstituted or substituted C₆-C₁₀ aryl,unsubstituted or substituted heterocyclyl comprising one or two 5- to8-membered rings and 1-4 heteroatoms selected from O, N, and S,unsubstituted or substituted heteroaryl comprising one or two 5- to8-membered rings and 1-4 heteroatoms selected from O, N, and S, S(O)₂R₂,C(O)R₂, OR₂, and NR₃R₄.

In a further embodiment,

is heteroaryl selected from pyrrolyl, pyrazolyl, imidazolyl, pyridinyl,and pyrimidinyl, each of which is optionally substituted. In a furtherembodiment,

is optionally substituted pyridinyl.

In one embodiment,

is unsubstituted heterocyclyl or heterocyclyl substituted with one ormore substituents independently selected from halogen, OH, cyano,unsubstituted or substituted C₁-C₆ alkyl, unsubstituted or substitutedC₁-C₆ alkoxy, unsubstituted or substituted C₆-C₁₀ aryl, andunsubstituted or substituted heteroaryl comprising one or two 5- to8-membered rings and 1-4 heteroatoms selected from O, N, and S. In afurther embodiment,

is heterocyclyl substituted with one or more substituents independentlyselected from unsubstituted or substituted C₆-C₁₀ aryl and unsubstitutedor substituted heteroaryl comprising one or two 5- to 8-membered ringsand 1-4 heteroatoms selected from O, N, and S.

In a further embodiment,

is heterocyclyl selected from pyrrolidinyl, piperidinyl, andpiperazinyl, each of which is optionally substituted. In a furtherembodiment,

is optionally substituted piperidinyl.

In one embodiment, a compound of formula A is a compound of formula I:

or a pharmaceutically acceptable salt thereof, wherein:

Z₁-Z₂ is C(O)—O, O—C(O), C(O)—S, S—C(O), C(O)—NR—NR, or NR—NR—C(O);

each R is independently H or C₁-C₃ alkyl;

n1 is 0, 1, 2, 3, or 4;

each R₁₁ is independently halogen, OH, unsubstituted or substitutedC₁-C₆ alkyl, unsubstituted or substituted C₁-C₆ alkoxy, C(O)OH,C(O)-(unsubstituted or substituted C₁-C₆ alkyl), C(O)-(unsubstituted orsubstituted C₁-C₆ alkoxy), C(O)NH-(unsubstituted or substituted C₁-C₆alkyl), S(O)_(p1)-(unsubstituted or substituted C₁-C₆ alkyl),unsubstituted or substituted C₃-C₈ cycloalkyl, unsubstituted orsubstituted C₆-C₁₀ aryl, unsubstituted or substituted heterocyclylcomprising one or two 5- to 8-membered rings s and 1-4 heteroatomsselected from O, N, and S, or unsubstituted or substituted heteroarylcomprising one or two 5- to 8-membered rings s and 1-4 heteroatomsselected from O, N, and S;

m1 is 0, 1, 2, 3, or 4;

each R₁₂ is independently halogen, OH, unsubstituted or substitutedC₁-C₆ alkyl, unsubstituted or substituted C₁-C₆ alkoxy, orC(O)-(unsubstituted or substituted C₁-C₆ alkyl);

o1 is 0, 1, 2, 3, 4, or 5;

each R₁₃ is independently halogen, OH, unsubstituted or substitutedC₁-C₆ alkyl, unsubstituted or substituted C₁-C₆ alkoxy,C(O)-(unsubstituted or substituted C₁-C₆ alkyl), orS(O)_(p1)-(unsubstituted or substituted C₁-C₆ alkyl); and

p1 is 0, 1, or 2.

In one embodiment, Z₁-Z₂ is C(O)—O, O—C(O), C(O)—S, or S—C(O).

In one embodiment, Z₁-Z₂ is C(O)—S, S—C(O), C(O)—NR—NR, or NR—NR—C(O).

In one embodiment, Z₁-Z₂ is C(O)—O or O—C(O).

In one embodiment, Z₁-Z₂ is C(O)—O.

In one embodiment, Z₁-Z₂ is C(O)—S or S—C(O).

In one embodiment, Z₁-Z₂ is C(O)—S.

In one embodiment, Z₁-Z₂ is C(O)—NR—NR or NR—NR—C(O).

In one embodiment, Z₁-Z₂ is C(O)—NR—NR.

In one embodiment, each R is H (i.e., Z₁-Z₂ is C(O)—NH—NH orNH—NH—C(O)).

In one embodiment, one of R is H, and the other R is C₁-C₃ alkyl (e.g.,methyl, ethyl, or propyl).

In one embodiment, each R is C₁-C₃ alkyl (e.g., methyl, ethyl, orpropyl).

In one embodiment, n1 is 0, 1, or 2.

In one embodiment, n1 is 0.

In one embodiment, n1 is 1.

In one embodiment, n1 is 2.

In one embodiment, n1 is 3.

In one embodiment, n1 is 4.

In one embodiment, at least one R₁₁ is independently halogen, OH,unsubstituted or substituted C₁-C₆ alkyl, unsubstituted or substitutedC₁-C₆ alkoxy, C(O)OH, C(O)-(unsubstituted or substituted C₁-C₆ alkyl),C(O)-(unsubstituted or substituted C₁-C₆ alkoxy), C(O)NH-(unsubstitutedor substituted C₁-C₆ alkyl), or S(O)_(p1)-(unsubstituted or substitutedC₁-C₆ alkyl).

In one embodiment, at least one R₁₁ is independently halogen, OH,unsubstituted or substituted C₁-C₆ alkyl, or unsubstituted orsubstituted C₁-C₆ alkoxy.

In one embodiment, at least one R₁₁ is halogen (e.g., F, Cl, Br, or I).

In one embodiment, at least one R₁₁ is OH.

In one embodiment, at least one R₁₁ is unsubstituted or substitutedstraight-chain C₁-C₆ alkyl or branched C₃-C₆ alkyl. In a furtherembodiment, at least one R₁₁ is methyl, ethyl, propyl, i-propyl, butyl,i-butyl, t-butyl, pentyl, or hexyl, each of which is optionallysubstituted with halogen (e.g., F, Cl, Br, or I).

In one embodiment, at least one R₁₁ is unsubstituted or substitutedstraight-chain C₁-C₆ alkoxy or branched C₃-C₆ alkoxy. In a furtherembodiment, at least one R₁₁ is methoxy, ethoxy, propoxy, i-propoxy,butoxy, i-butoxy, t-butoxy, pentoxy, or hexyloxy, each of which isoptionally substituted with halogen (e.g., F, Cl, Br, or I).

In one embodiment, at least one R₁₁ is C(O)OH.

In one embodiment, at least one R₁₁ is C(O)-(unsubstituted orsubstituted C₁-C₆ alkyl), wherein the unsubstituted or substituted C₁-C₆alkyl is selected from methyl, ethyl, propyl, i-propyl, butyl, i-butyl,t-butyl, pentyl, and hexyl, each of which is optionally substituted withhalogen (e.g., F, Cl, Br, or I).

In one embodiment, at least one R₁₁ is C(O)-(unsubstituted orsubstituted C₁-C₆ alkoxy), wherein the unsubstituted or substitutedC₁-C₆ alkoxy is selected from methoxy, ethoxy, propoxy, i-propoxy,butoxy, i-butoxy, t-butoxy, pentoxy, and hexyloxy, each of which isoptionally substituted with halogen (e.g., F, Cl, Br, or I).

In one embodiment, at least one R₁₁ is C(O)NH-(unsubstituted orsubstituted C₁-C₆ alkyl), wherein the unsubstituted or substituted C₁-C₆alkyl is selected from methyl, ethyl, propyl, i-propyl, butyl, i-butyl,t-butyl, pentyl, and hexyl, each of which is optionally substituted withhalogen (e.g., F, Cl, Br, or I).

In one embodiment, at least one R₁₁ is S(O)_(p1)-(unsubstituted orsubstituted C₁-C₆ alkyl). In a further embodiment, at least one R₁₁ isS-(unsubstituted or substituted C₁-C₆ alkyl). In another furtherembodiment, at least one R₁₁ is S(O)-(unsubstituted or substituted C₁-C₆alkyl). In another further embodiment, at least one R₁₁ isS(O)₂-(unsubstituted or substituted C₁-C₆ alkyl). In a furtherembodiment, the unsubstituted or substituted C₁-C₆ alkyl is selectedfrom methyl, ethyl, propyl, i-propyl, butyl, i-butyl, t-butyl, pentyl,and hexyl, each of which is optionally substituted with halogen (e.g.,F, Cl, Br, or I).

In one embodiment, at least one R₁₁ is C₃-C₈ cycloalkyl selected fromcyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, andcyclooctyl, each of which is optionally substituted with one or moresubstituents independently selected from halogen, OH, cyano, nitro,C₁-C₆ alkyl, C₁-C₆ alkoxy, and amino.

In one embodiment, at least one R₁₁ is phenyl optionally substitutedwith one or more substituents independently selected from halogen, OH,cyano, nitro, C₁-C₆ alkyl, C₁-C₆ alkoxy, and amino.

In one embodiment, at least one R₁₁ is heterocyclyl optionallysubstituted with one or more substituents independently selected fromhalogen, OH, cyano, nitro, C₁-C₆ alkyl, C₁-C₆ alkoxy, and amino. In afurther embodiment, at least one R₁₁ is heterocyclyl comprising a 5- or6-membered ring optionally substituted with one or more substituentsindependently selected from halogen, OH, cyano, nitro, C₁-C₆ alkyl,C₁-C₆ alkoxy, and amino.

In one embodiment, at least one R₁₁ is heteroaryl optionally substitutedwith one or more substituents independently selected from halogen, OH,cyano, nitro, C₁-C₆ alkyl, C₁-C₆ alkoxy, and amino. In a furtherembodiment, at least one R₁₁ is heteroaryl comprising a 5- or 6-memberedring optionally substituted with one or more substituents independentlyselected from halogen, OH, cyano, nitro, C₁-C₆ alkyl, C₁-C₆ alkoxy, andamino.

In one embodiment, m1 is 0, 1, or 2.

In one embodiment, m1 is 0.

In one embodiment, m1 is 1.

In one embodiment, m1 is 2.

In one embodiment, m1 is 3.

In one embodiment, m1 is 4.

In one embodiment, at least one R₁₂ is halogen (e.g., F, Cl, Br, or I).In a further embodiment, at least one R₁₂ is C₁.

In one embodiment, at least one R₁₂ is OH.

In one embodiment, at least one R₁₂ is unsubstituted or substitutedstraight-chain C₁-C₆ alkyl or branched C₃-C₆ alkyl. In a furtherembodiment, at least one R₁₂ is methyl, ethyl, propyl, i-propyl, butyl,i-butyl, t-butyl, pentyl, or hexyl, each of which is optionallysubstituted with halogen (e.g., F, Cl, Br, or I), amino, nitro, C₁-C₆alkylsulfonyl, or C₁-C₆ alkoxy.

In one embodiment, at least one R₁₂ is unsubstituted or substitutedstraight-chain C₁-C₆ alkoxy or branched C₃-C₆ alkoxy. In a furtherembodiment, at least one R₁₂ is methoxy, ethoxy, propoxy, i-propoxy,butoxy, i-butoxy, t-butoxy, pentoxy, or hexyloxy, each of which isoptionally substituted with halogen (e.g., F, Cl, Br, or I).

In one embodiment, at least one R₁₂ is C(O)-(unsubstituted orsubstituted C₁-C₆ alkyl), wherein the unsubstituted or substituted C₁-C₆alkyl is selected from methyl, ethyl, propyl, i-propyl, butyl, i-butyl,t-butyl, pentyl, and hexyl, each of which is optionally substituted withhalogen (e.g., F, Cl, Br, or I), amino, nitro, C₁-C₆ alkylsulfonyl, orC₁-C₆ alkoxy.

In one embodiment, o1 is 0, 1, or 2.

In one embodiment, o1 is 0.

In one embodiment, o1 is 1.

In one embodiment, o1 is 2.

In one embodiment, o1 is 3.

In one embodiment, o1 is 4.

In one embodiment, o1 is 5.

In one embodiment, at least one R₁₃ is halogen (e.g., F, Cl, Br, or I).In a further embodiment, at least one R₁₃ is C₁.

In one embodiment, at least one R₁₃ is OH.

In one embodiment, at least one R₁₃ is unsubstituted or substitutedstraight-chain C₁-C₆ alkyl or branched C₃-C₆ alkyl. In a furtherembodiment, at least one R₁₃ is methyl, ethyl, propyl, i-propyl, butyl,i-butyl, t-butyl, pentyl, or hexyl, each of which is optionallysubstituted with halogen (e.g., F, Cl, Br, or I).

In one embodiment, at least one R₁₃ is unsubstituted or substitutedstraight-chain C₁-C₆ alkoxy or branched C₃-C₆ alkoxy. In a furtherembodiment, at least one R₁₃ is methoxy, ethoxy, propoxy, i-propoxy,butoxy, i-butoxy, t-butoxy, pentoxy, or hexyloxy, each of which isoptionally substituted with halogen (e.g., F, Cl, Br, or I).

In one embodiment, at least one R₁₃ is C(O)-(unsubstituted orsubstituted C₁-C₆ alkyl), wherein the unsubstituted or substituted C₁-C₆alkyl is selected from methyl, ethyl, propyl, i-propyl, butyl, i-butyl,t-butyl, pentyl, and hexyl, each of which is optionally substituted withhalogen (e.g., F, Cl, Br, or I).

In one embodiment, at least one R₁₃ is S(O)_(p1)-(unsubstituted orsubstituted C₁-C₆ alkyl). In a further embodiment, at least one R₁₃ isS-(unsubstituted or substituted C₁-C₆ alkyl). In another furtherembodiment, at least one R₁₃ is S(O)-(unsubstituted or substituted C₁-C₆alkyl). In another further embodiment, at least one R₁₃ isS(O)₂-(unsubstituted or substituted C₁-C₆ alkyl). In a furtherembodiment, the unsubstituted or substituted C₁-C₆ alkyl is selectedfrom methyl, ethyl, propyl, i-propyl, butyl, i-butyl, t-butyl, pentyl,and hexyl, each of which is optionally substituted with halogen (e.g.,F, Cl, Br, or I). In a further embodiment, at least one R₁₃ isS(O)₂—CH₃.

In one embodiment, p1 is 0.

In one embodiment, p1 is 1.

In one embodiment, p1 is 2.

Any of the groups described above for any of Z₁, Z₂, R, R₁₁, R₁₂, R₁₃,n1, m1, o1, and p1 can be combined with any of the groups describedabove for one or more of the remainder of Z₁, Z₂, R, R₁₁, R₁₂, R₁₃, n1,m1, o1, and p1.

In one embodiment, Z₁-Z₂ is C(O)—O or O—C(O); n1 is 0; m1 is 0 or 1; R₁₂is halogen (e.g., F, Cl, Br, or I); o1 is 0, 1, or 2; and R₁₃ is halogen(e.g., F, Cl, Br, or I), unsubstituted or substituted straight-chainC₁-C₆ alkyl or branched C₃-C₆ alkyl, or S(O)_(p1)-(unsubstituted orsubstituted C₁-C₆ alkyl). In a further embodiment, R₁₂ is F or Cl; andR₁₃ is F, Cl, methyl, ethyl, propyl, or S(O)₂-(unsubstituted orsubstituted C₁-C₆ alkyl). In a further embodiment, R₁₂ is C₁; o1 is 2;and R₁₃ is Cl or S(O)₂—CH₃.

In one embodiment, Z₁-Z₂ is C(O)—O; n1 is 0; m1 is 0 or 1; R₁₂ ishalogen (e.g., F, Cl, Br, or I); o1 is 0, 1, or 2; and R₁₃ is halogen(e.g., F, Cl, Br, or I), unsubstituted or substituted straight-chainC₁-C₆ alkyl or branched C₃-C₆ alkyl, or S(O)_(p1)-(unsubstituted orsubstituted C₁-C₆ alkyl). In a further embodiment, R₁₂ is F or Cl; andR₁₃ is F, Cl, methyl, ethyl, propyl, or S(O)₂-(unsubstituted orsubstituted C₁-C₆ alkyl). In a further embodiment, R₁₂ is C₁; o1 is 2;and R₁₃ is Cl or S(O)₂—CH₃.

In one embodiment, Z₁-Z₂ is C(O)—S or S—C(O); n1 is 0; m1 is 0 or 1; R₁₂is halogen (e.g., F, Cl, Br, or I); o1 is 0, 1, or 2; and R₁₃ is halogen(e.g., F, Cl, Br, or I), unsubstituted or substituted straight-chainC₁-C₆ alkyl or branched C₃-C₆ alkyl, or S(O)_(p1)-(unsubstituted orsubstituted C₁-C₆ alkyl). In a further embodiment, R₁₂ is F or Cl; andR₁₃ is F, Cl, methyl, ethyl, propyl, or S(O)₂-(unsubstituted orsubstituted C₁-C₆ alkyl). In a further embodiment, R₁₂ is C₁; o1 is 2;and R₁₃ is Cl or S(O)₂—CH₃.

In one embodiment, Z₁-Z₂ is C(O)—S; n1 is 0; m1 is 0 or 1; R₁₂ ishalogen (e.g., F, Cl, Br, or I); o1 is 0, 1, or 2; and R₁₃ is halogen(e.g., F, Cl, Br, or I), unsubstituted or substituted straight-chainC₁-C₆ alkyl or branched C₃-C₆ alkyl, or S(O)_(p1)-(unsubstituted orsubstituted C₁-C₆ alkyl). In a further embodiment, R₁₂ is F or Cl; andR₁₃ is F, Cl, methyl, ethyl, propyl, or S(O)₂-(unsubstituted orsubstituted C₁-C₆ alkyl). In a further embodiment, R₁₂ is C₁; o1 is 2;and R₁₃ is Cl or S(O)₂—CH₃.

In one embodiment, Z₁-Z₂ is C(O)—NH—NH or NH—NH—C(O); n1 is 0; m1 is 0or 1; R₁₂ is halogen (e.g., F, Cl, Br, or I); o1 is 0, 1, or 2; and R₁₃is halogen (e.g., F, Cl, Br, or I), unsubstituted or substitutedstraight-chain C₁-C₆ alkyl or branched C₃-C₆ alkyl, orS(O)_(p1)-(unsubstituted or substituted C₁-C₆ alkyl). In a furtherembodiment, R₁₂ is F or Cl; and R₁₃ is F, Cl, methyl, ethyl, propyl, orS(O)₂-(unsubstituted or substituted C₁-C₆ alkyl). In a furtherembodiment, R₁₂ is C₁; o1 is 2; and R₁₃ is Cl or S(O)₂—CH₃.

In one embodiment, Z₁-Z₂ is C(O)—NH—NH; n1 is 0; m1 is 0 or 1; R₁₂ ishalogen (e.g., F, Cl, Br, or I); o1 is 0, 1, or 2; and R₁₃ is halogen(e.g., F, Cl, Br, or I), unsubstituted or substituted straight-chainC₁-C₆ alkyl or branched C₃-C₆ alkyl, or S(O)_(p1)-(unsubstituted orsubstituted C₁-C₆ alkyl). In a further embodiment, R₁₂ is F or Cl; andR₁₃ is F, Cl, methyl, ethyl, propyl, or S(O)₂-(unsubstituted orsubstituted C₁-C₆ alkyl). In a further embodiment, R₁₂ is C₁; o1 is 2;and R₁₃ is Cl or S(O)₂—CH₃.

In one embodiment, a compound of formula I is a compound of formula Ia:

or a pharmaceutically acceptable salt thereof, wherein Z₃ is O, S, orNR—NR; and R, R₁₂, R₁₃, and p1 are each as defined above in formula I.

In one embodiment, Z₃ is O.

In one embodiment, Z₃ is S.

In one embodiment, Z₃ is NR.

In one embodiment, R₁₂ is halogen. In a further embodiment, R₁₂ is F orCl. In a further embodiment, R₁₂ is C₁.

In one embodiment, at least one R₁₃ is halogen. In a further embodiment,at least one R₁₃ is F or Cl. In a further embodiment, at least one R₁₃is C₁.

In one embodiment, at least one R₁₃ is S(O)₂-(unsubstituted orsubstituted C₁-C₆ alkyl), wherein the unsubstituted or substituted C₁-C₆alkyl is selected from methyl, ethyl, propyl, i-propyl, butyl, i-butyl,t-butyl, pentyl, and hexyl, each of which is optionally substituted withhalogen (e.g., F, Cl, Br, or I). In a further embodiment, at least oneR₁₃ is S(O)₂—CH₃.

In one embodiment, one R₁₃ is halogen, and the other R₁₃ isS(O)₂-(unsubstituted or substituted C₁-C₆ alkyl), wherein theunsubstituted or substituted C₁-C₆ alkyl is selected from methyl, ethyl,propyl. In a further embodiment, one R₁₃ is Cl, and the other R₁₃ isS(O)₂—CH₃.

Any of Z₃, R, R₁₂ and R₁₃, and p1 can be selected from any of the groupsdescribed above and combined with any of the groups described above forone or more of the remainder of Z₃, R, R₁₂ and R₁₃, and p1.

In one embodiment, a compound of formula A is a compound of formula II:

or a pharmaceutically acceptable salt thereof, wherein:

Z₁-Z₂ is C(O)—O, O—C(O), C(O)—S, S—C(O), C(O)—NR—NR, or NR—NR—C(O);

each R is independently H or C₁-C₃ alkyl;

Y₁ and Y₂ are each independently N or CR₂₄;

each R₂₄ is independently H, halogen, cyano, unsubstituted orsubstituted C₁-C₆ alkyl, or unsubstituted or substituted C₁-C₆ alkoxy;

n2 is 0, 1, 2, 3, 4, or 5;

each R₂₁ is independently halogen, cyano, unsubstituted or substitutedC₁-C₆ alkyl, unsubstituted or substituted C₁-C₆ alkoxy,S(O)_(o2)-(unsubstituted or substituted C₁-C₆ alkyl), amino, di-C₁-C₆alkylamino, or unsubstituted or substituted C₆-C₁₀ aryl;

o2 is 0, 1, or 2;

m2 is 0, 1, 2, 3, or 4;

each R₂₂ is independently halogen, unsubstituted or substituted C₁-C₆alkyl, or unsubstituted or substituted C₁-C₆ alkoxy;

R₂₃ is R₂₅, S(O)₂R₂₅, C(O)R₂₅, OR₂₅, or NR₂₆R₂₇;

R₂₅ is unsubstituted or substituted C₃-C₈ cycloalkyl, unsubstituted orsubstituted C₆-C₁₀ aryl, unsubstituted or substituted heterocyclylcomprising one or two 5- to 8-membered rings and 1-4 heteroatomsselected from O, N, and S, or unsubstituted or substituted heteroarylcomprising one or two 5- to 8-membered rings and 1-4 heteroatomsselected from O, N, and S; and

R₂₆ and R₂₇ are each independently H or unsubstituted or substitutedC₁-C₆ alkyl.

In one embodiment, Z₁-Z₂ is C(O)—O, O—C(O), C(O)—S, or S—C(O).

In one embodiment, Z₁-Z₂ is C(O)—S, S—C(O), C(O)—NR—NR, or NR—NR—C(O).

In one embodiment, Z₁-Z₂ is C(O)—O or O—C(O).

In one embodiment, Z₁-Z₂ is C(O)—O.

In one embodiment, Z₁-Z₂ is C(O)—S or S—C(O).

In one embodiment, Z₁-Z₂ is C(O)—S.

In one embodiment, Z₁-Z₂ is C(O)—NR—NR or NR—NR—C(O).

In one embodiment, Z₁-Z₂ is C(O)—NR—NR.

In one embodiment, each R is H (i.e., Z₁-Z₂ is C(O)—NH—NH orNH—NH—C(O)).

In one embodiment, one of R is H, and the other R is C₁-C₃ alkyl (e.g.,methyl, ethyl, or propyl).

In one embodiment, each R is C₁-C₃ alkyl (e.g., methyl, ethyl, orpropyl).

In one embodiment, Y₁ is N and Y₂ is N.

In one embodiment, Y₁ is N and Y₂ is CR₂₄. In a further embodiment, R₂₄is H. In another further embodiment, R₂₄ is halogen (e.g., F, Cl, Br, orI), cyano, unsubstituted or substituted C₁-C₆ alkyl (e.g., methyl,ethyl, propyl, i-propyl, butyl, i-butyl, t-butyl, pentyl, or hexyl, eachof which is optionally substituted with halogen (e.g., F, Cl, Br, orI)), or unsubstituted or substituted C₁-C₆ alkoxy (e.g., methoxy,ethoxy, propoxy, i-propoxy, butoxy, i-butoxy, t-butoxy, pentoxy, orhexyloxy, each of which is optionally substituted with halogen (e.g., F,Cl, Br, or I)).

In one embodiment, Y₁ is CR₂₄ and Y₂ is CR₂₄. In a further embodiment,each R₂₄ is H. In another further embodiment, one R₂₄ is H, and theother R₂₄ is halogen (e.g., F, Cl, Br, or I), cyano, unsubstituted orsubstituted C₁-C₆ alkyl (e.g., methyl, ethyl, propyl, i-propyl, butyl,i-butyl, t-butyl, pentyl, or hexyl, each of which is optionallysubstituted with halogen (e.g., F, Cl, Br, or I)), or unsubstituted orsubstituted C₁-C₆ alkoxy (e.g., methoxy, ethoxy, propoxy, i-propoxy,butoxy, i-butoxy, t-butoxy, pentoxy, or hexyloxy, each of which isoptionally substituted with halogen (e.g., F, Cl, Br, or I)). In anotherfurther embodiment, each R₂₄ is independently halogen (e.g., F, Cl, Br,or I), cyano, unsubstituted or substituted C₁-C₆ alkyl (e.g., methyl,ethyl, propyl, i-propyl, butyl, i-butyl, t-butyl, pentyl, or hexyl, eachof which is optionally substituted with halogen (e.g., F, Cl, Br, orI)), or unsubstituted or substituted C₁-C₆ alkoxy (e.g., methoxy,ethoxy, propoxy, i-propoxy, butoxy, i-butoxy, t-butoxy, pentoxy, orhexyloxy, each of which is optionally substituted with halogen (e.g., F,Cl, Br, or I)).

In one embodiment, n2 is 0, 1, or 2.

In one embodiment, n2 is 0.

In one embodiment, n2 is 1.

In one embodiment, n2 is 2.

In one embodiment, n2 is 3.

In one embodiment, n2 is 4.

In one embodiment, n2 is 5.

In one embodiment, at least one R₂₁ is halogen (e.g., F, Cl, Br, or I).

In one embodiment, at least one R₂₁ is cyano.

In one embodiment, at least one R₂₁ is unsubstituted or substitutedstraight-chain C₁-C₆ alkyl or branched C₃-C₆ alkyl. In a furtherembodiment, R₂₁ is methyl, ethyl, propyl, propyl, butyl, i-butyl,t-butyl, pentyl, or hexyl, each of which is optionally substituted withhalogen (e.g., F, Cl, Br, or I).

In one embodiment, at least one R₂₁ is unsubstituted or substitutedstraight-chain C₁-C₆ alkoxy or branched C₃-C₆ alkoxy. In a furtherembodiment, at least one R₂₁ is methoxy, ethoxy, propoxy, i-propoxy,butoxy, i-butoxy, t-butoxy, pentoxy, or hexyloxy, each of which isoptionally substituted with halogen (e.g., F, Cl, Br, or I). In afurther embodiment, at least one R₂₁ is trifluoromethoxy.

In one embodiment, at least one R₂₁ is S(O)_(o2)-(unsubstituted orsubstituted C₁-C₆ alkyl). In a further embodiment, at least one R₂₁ isS-(unsubstituted or substituted C₁-C₆ alkyl). In another furtherembodiment, at least one R₂₁ is S(O)-(unsubstituted or substituted C₁-C₆alkyl). In another further embodiment, at least one R₂₁ isS(O)₂-(unsubstituted or substituted C₁-C₆ alkyl). In a furtherembodiment, the unsubstituted or substituted C₁-C₆ alkyl is selectedfrom methyl, ethyl, propyl, i-propyl, butyl, i-butyl, t-butyl, pentyl,and hexyl, each of which is optionally substituted with halogen (e.g.,F, Cl, Br, or I).

In one embodiment, o2 is 0.

In one embodiment, o2 is 1.

In one embodiment, o2 is 2.

In one embodiment, at least one R₂₁ is dimethylamino, diethylamino, ordipropylamino.

In one embodiment, at least one R₂₁ is phenyl optionally substitutedwith one or more substituents independently selected from halogen, OH,cyano, nitro, C₁-C₆ alkyl, C₁-C₆ alkoxy, and amino.

In one embodiment, m2 is 0, 1, or 2.

In one embodiment, m2 is 0.

In one embodiment, m2 is 1.

In one embodiment, m2 is 2.

In one embodiment, m2 is 3.

In one embodiment, m2 is 4.

In one embodiment, at least one R₂₂ is halogen (e.g., F, Cl, Br, or I).

In one embodiment, at least one R₂₂ is unsubstituted or substitutedstraight-chain C₁-C₆ alkyl or branched C₃-C₆ alkyl. In a furtherembodiment, at least one R₂₂ is methyl, ethyl, propyl, i-propyl, butyl,i-butyl, t-butyl, pentyl, or hexyl, each of which is optionallysubstituted with halogen (e.g., F, Cl, Br, or I). In one embodiment, atleast one R₂₂ is methyl.

In one embodiment, at least one R₂₂ is unsubstituted or substitutedstraight-chain C₁-C₆ alkoxy or branched C₃-C₆ alkoxy. In a furtherembodiment, at least one R₂₂ is methoxy, ethoxy, propoxy, i-propoxy,butoxy, i-butoxy, t-butoxy, pentoxy, or hexyloxy, each of which isoptionally substituted with halogen (e.g., F, Cl, Br, or I).

In one embodiment, R₂₃ is C₃-C₈ cycloalkyl selected from cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl, eachof which is optionally substituted with one or more substituentsindependently selected from halogen, OH, cyano, nitro, C₁-C₆ alkyl,C₁-C₆ alkoxy, and amino.

In one embodiment, R₂₃ is phenyl optionally substituted with one or moresubstituents independently selected from halogen, OH, cyano, nitro,C₁-C₆ alkyl, C₁-C₆ alkoxy, and amino.

In one embodiment, R₂₃ is heterocyclyl optionally substituted with oneor more substituents independently selected from halogen, OH, cyano,nitro, C₁-C₆ alkyl, C₁-C₆ alkoxy, and amino. In a further embodiment,R₂₃ is heterocyclyl comprising a 5- or 6-membered ring optionallysubstituted with one or more substituents independently selected fromhalogen, OH, cyano, nitro, C₁-C₆ alkyl, C₁-C₆ alkoxy, and amino. In afurther embodiment, R₂₃ is heterocyclyl selected from piperidinyl,piperazinyl, or morpholinyl, each of which is optionally substitutedwith one or more substituents independently selected from halogen, OH,cyano, nitro, C₁-C₆ alkyl, C₁-C₆ alkoxy, and amino. In a furtherembodiment, R₂₃ is morpholinyl optionally substituted with one or moresubstituents independently selected from halogen, OH, cyano, nitro,C₁-C₆ alkyl, C₁-C₆ alkoxy, and amino. In a further embodiment, R₂₃ ismorpholinyl substituted with two substituents independently selectedfrom methyl, ethyl, or propyl.

In one embodiment, R₂₃ is heteroaryl optionally substituted with one ormore substituents independently selected from halogen, OH, cyano, nitro,C₁-C₆ alkyl, C₁-C₆ alkoxy, and amino. In a further embodiment, R₂₃ isheteroaryl comprising a 5- or 6-membered ring optionally substitutedwith one or more substituents independently selected from halogen, OH,cyano, nitro, C₁-C₆ alkyl, C₁-C₆ alkoxy, and amino.

In one embodiment, R₂₃ is S(O)₂R₂₅ or C(O)R₂₅.

In one embodiment, R₂₃ is OR₂₅ or NR₂₆R₂₇

In one embodiment, R₂₃ is S(O)₂R₂₅.

In one embodiment, R₂₃ is C(O)R₂₅.

In one embodiment, R₂₃ is OR₂₅.

In one embodiment, R₂₃ is NR₂₆R₂₇.

In one embodiment, R₂₅ is C₃-C₈ cycloalkyl selected from cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl, eachof which is optionally substituted with one or more substituentsindependently selected from halogen, OH, cyano, nitro, C₁-C₆ alkyl,C₁-C₆ alkoxy, and amino.

In one embodiment, R₂₅ is phenyl optionally substituted with one or moresubstituents independently selected from halogen, OH, cyano, nitro,C₁-C₆ alkyl, C₁-C₆ alkoxy, and amino.

In one embodiment, R₂₅ is heterocyclyl optionally substituted with oneor more substituents independently selected from halogen, OH, cyano,nitro, C₁-C₆ alkyl, C₁-C₆ alkoxy, and amino. In a further embodiment,R₂₅ is heterocyclyl comprising a 5- or 6-membered ring optionallysubstituted with one or more substituents independently selected fromhalogen, OH, cyano, nitro, C₁-C₆ alkyl, C₁-C₆ alkoxy, and amino.

In one embodiment, R₂₅ is heteroaryl optionally substituted with one ormore substituents independently selected from halogen, OH, cyano, nitro,C₁-C₆ alkyl, C₁-C₆ alkoxy, and amino. In a further embodiment, R₂₅ isheteroaryl comprising a 5- or 6-membered ring optionally substitutedwith one or more substituents independently selected from halogen, OH,cyano, nitro, C₁-C₆ alkyl, C₁-C₆ alkoxy, and amino.

In one embodiment, R₂₆ and R₂₇ are each H.

In one embodiment, one of R₂₆ and R₂₇ is H, and the other isunsubstituted or substituted straight-chain C₁-C₆ alkyl or branchedC₃-C₆ alkyl. In a further embodiment, one of R₂₆ and R₂₇ is H, and theother is methyl, ethyl, propyl, i-propyl, butyl, i-butyl, t-butyl,pentyl, or hexyl, each of which is optionally substituted with halogen(e.g., F, Cl, Br, or I).

In one embodiment, R₂₆ and R₂₇ are each independently unsubstituted orsubstituted straight-chain C₁-C₆ alkyl or branched C₃-C₆ alkyl. In afurther embodiment, R₂₆ and R₂₇ are each independently methyl, ethyl,propyl, i-propyl, butyl, i-butyl, t-butyl, pentyl, or hexyl, each ofwhich is optionally substituted with halogen (e.g., F, Cl, Br, or I).

Any of the groups described above for any of Z₁, Z₂, Y₁, Y₂, R, R₂₁,R₂₂, R₂₃, R₂₄, R₂₅, R₂₆, R₂₇, n2, m2, and o2 can be combined with any ofthe groups described above for one or more of the remainder of Z₁, Z₂,Y₁, Y₂, R, R₂₁, R₂₂, R₂₃, R₂₄, R₂₅, R₂₆, R₂₇, n2, m2, and o2.

In one embodiment, Z₁-Z₂ is C(O)—O or O—C(O); Y₁ is N and Y₂ is CR₂₄; n2is 0 or 1; m2 is 0 or 1; R₂₁ is unsubstituted or substituted C₁-C₆ alkylor unsubstituted or substituted C₁-C₆ alkoxy; R₂₂ is unsubstituted orsubstituted C₁-C₆ alkyl or unsubstituted or substituted C₁-C₆ alkoxy. Ina further embodiment, R₂₄ is H. In a further embodiment, R₂₃ isunsubstituted or substituted C₃-C₈ cycloalkyl, unsubstituted orsubstituted C₆-C₁₀ aryl, unsubstituted or substituted heterocyclylcomprising one or two 5- to 8-membered rings and 1-4 heteroatomsselected from O, N, and S, or unsubstituted or substituted heteroarylcomprising one or two 5- to 8-membered rings and 1-4 heteroatomsselected from O, N, and S. In a further embodiment, R₂₃ is unsubstitutedor substituted C₃-C₈ cycloalkyl or unsubstituted or substitutedheterocyclyl comprising one or two 5- to 8-membered rings and 1-4heteroatoms selected from O, N, and S. In a further embodiment, R₂₃ isunsubstituted or substituted heterocyclyl comprising one or two 5- to8-membered rings and 1-4 heteroatoms selected from O, N, and S. In afurther embodiment, R₂₃ is unsubstituted or substituted morpholinyl.

In one embodiment, Z₁-Z₂ is C(O)—O; Y₁ is N and Y₂ is CR₂₄; n2 is 0 or1; m2 is 0 or 1; R₂₁ is unsubstituted or substituted C₁-C₆ alkyl orunsubstituted or substituted C₁-C₆ alkoxy; R₂₂ is unsubstituted orsubstituted C₁-C₆ alkyl or unsubstituted or substituted C₁-C₆ alkoxy. Ina further embodiment, R₂₄ is H. In a further embodiment, R₂₃ isunsubstituted or substituted C₃-C₈ cycloalkyl, unsubstituted orsubstituted C₆-C₁₀ aryl, unsubstituted or substituted heterocyclylcomprising one or two 5- to 8-membered rings and 1-4 heteroatomsselected from O, N, and S, or unsubstituted or substituted heteroarylcomprising one or two 5- to 8-membered rings and 1-4 heteroatomsselected from O, N, and S. In a further embodiment, R₂₃ is unsubstitutedor substituted C₃-C₈ cycloalkyl or unsubstituted or substitutedheterocyclyl comprising one or two 5- to 8-membered rings and 1-4heteroatoms selected from O, N, and S. In a further embodiment, R₂₃ isunsubstituted or substituted heterocyclyl comprising one or two 5- to8-membered rings and 1-4 heteroatoms selected from O, N, and S. In afurther embodiment, R₂₃ is unsubstituted or substituted morpholinyl.

In one embodiment, Z₁-Z₂ is C(O)—S or S—C(O); Y₁ is N and Y₂ is CR₂₄; n2is 0 or 1; m2 is 0 or 1; R₂₁ is unsubstituted or substituted C₁-C₆ alkylor unsubstituted or substituted C₁-C₆ alkoxy; R₂₂ is unsubstituted orsubstituted C₁-C₆ alkyl or unsubstituted or substituted C₁-C₆ alkoxy. Ina further embodiment, R₂₄ is H. In a further embodiment, R₂₃ isunsubstituted or substituted C₃-C₈ cycloalkyl, unsubstituted orsubstituted C₆-C₁₀ aryl, unsubstituted or substituted heterocyclylcomprising one or two 5- to 8-membered rings and 1-4 heteroatomsselected from O, N, and S, or unsubstituted or substituted heteroarylcomprising one or two 5- to 8-membered rings and 1-4 heteroatomsselected from O, N, and S. In a further embodiment, R₂₃ is unsubstitutedor substituted C₃-C₈ cycloalkyl or unsubstituted or substitutedheterocyclyl comprising one or two 5- to 8-membered rings and 1-4heteroatoms selected from O, N, and S. In a further embodiment, R₂₃ isunsubstituted or substituted heterocyclyl comprising one or two 5- to8-membered rings and 1-4 heteroatoms selected from O, N, and S. In afurther embodiment, R₂₃ is unsubstituted or substituted morpholinyl.

In one embodiment, Z₁-Z₂ is C(O)—S; Y₁ is N and Y₂ is CR₂₄; n2 is 0 or1; m2 is 0 or 1; R₂₁ is unsubstituted or substituted C₁-C₆ alkyl orunsubstituted or substituted C₁-C₆ alkoxy; R₂₂ is unsubstituted orsubstituted C₁-C₆ alkyl or unsubstituted or substituted C₁-C₆ alkoxy. Ina further embodiment, R₂₄ is H. In a further embodiment, R₂₃ isunsubstituted or substituted C₃-C₈ cycloalkyl, unsubstituted orsubstituted C₆-C₁₀ aryl, unsubstituted or substituted heterocyclylcomprising one or two 5- to 8-membered rings and 1-4 heteroatomsselected from O, N, and S, or unsubstituted or substituted heteroarylcomprising one or two 5- to 8-membered rings and 1-4 heteroatomsselected from O, N, and S. In a further embodiment, R₂₃ is unsubstitutedor substituted C₃-C₈ cycloalkyl or unsubstituted or substitutedheterocyclyl comprising one or two 5- to 8-membered rings and 1-4heteroatoms selected from O, N, and S. In a further embodiment, R₂₃ isunsubstituted or substituted heterocyclyl comprising one or two 5- to8-membered rings and 1-4 heteroatoms selected from O, N, and S. In afurther embodiment, R₂₃ is unsubstituted or substituted morpholinyl.

In one embodiment, Z₁-Z₂ is C(O)—NH—NH or NH—NH—C(O); Y₁ is N and Y₂ isCR₂₄; n2 is 0 or 1; m2 is 0 or 1; R₂₁ is unsubstituted or substitutedC₁-C₆ alkyl or unsubstituted or substituted C₁-C₆ alkoxy; R₂₂ isunsubstituted or substituted C₁-C₆ alkyl or unsubstituted or substitutedC₁-C₆ alkoxy. In a further embodiment, R₂₄ is H. In a furtherembodiment, R₂₃ is unsubstituted or substituted C₃-C₈ cycloalkyl,unsubstituted or substituted C₆-C₁₀ aryl, unsubstituted or substitutedheterocyclyl comprising one or two 5- to 8-membered rings and 1-4heteroatoms selected from O, N, and S, or unsubstituted or substitutedheteroaryl comprising one or two 5- to 8-membered rings and 1-4heteroatoms selected from O, N, and S. In a further embodiment, R₂₃ isunsubstituted or substituted C₃-C₈ cycloalkyl or unsubstituted orsubstituted heterocyclyl comprising one or two 5- to 8-membered ringsand 1-4 heteroatoms selected from 0, N, and S. In a further embodiment,R₂₃ is unsubstituted or substituted heterocyclyl comprising one or two5- to 8-membered rings and 1-4 heteroatoms selected from O, N, and S. Ina further embodiment, R₂₃ is unsubstituted or substituted morpholinyl.

In one embodiment, Z₁-Z₂ is C(O)—NH—NH; Y₁ is N and Y₂ is CR₂₄; n2 is 0or 1; m2 is 0 or 1; R₂₁ is unsubstituted or substituted C₁-C₆ alkyl orunsubstituted or substituted C₁-C₆ alkoxy; R₂₂ is unsubstituted orsubstituted C₁-C₆ alkyl or unsubstituted or substituted C₁-C₆ alkoxy. Ina further embodiment, R₂₄ is H. In a further embodiment, R₂₃ isunsubstituted or substituted C₃-C₈ cycloalkyl, unsubstituted orsubstituted C₆-C₁₀ aryl, unsubstituted or substituted heterocyclylcomprising one or two 5- to 8-membered rings and 1-4 heteroatomsselected from O, N, and S, or unsubstituted or substituted heteroarylcomprising one or two 5- to 8-membered rings and 1-4 heteroatomsselected from O, N, and S. In a further embodiment, R₂₃ is unsubstitutedor substituted C₃-C₈ cycloalkyl or unsubstituted or substitutedheterocyclyl comprising one or two 5- to 8-membered rings and 1-4heteroatoms selected from O, N, and S. In a further embodiment, R₂₃ isunsubstituted or substituted heterocyclyl comprising one or two 5- to8-membered rings and 1-4 heteroatoms selected from O, N, and S. In afurther embodiment, R₂₃ is unsubstituted or substituted morpholinyl.

In one embodiment, a compound of formula II is a compound of formulaIIa:

or a pharmaceutically acceptable salt thereof, wherein:

Z₃ is O, S, or NR—NR;

p2 is 0, 1, 2, 3, or 4;

each R₂₈ is independently unsubstituted or substituted C₁-C₆ alkyl; and

R, R₂₁, R₂₂, n2, m2, and o2 are each as defined above in formula II.

In one embodiment, Z₃ is O.

In one embodiment, Z₃ is S.

In one embodiment, Z₃ is NR.

In one embodiment, p2 is 0, 1, or 2.

In one embodiment, p2 is 0.

In one embodiment, p2 is 1.

In one embodiment, p2 is 2.

In one embodiment, p2 is 3.

In one embodiment, p2 is 4.

In one embodiment, each R₂₈ is independently unsubstituted orsubstituted straight-chain C₁-C₆ alkyl or branched C₃-C₆ alkyl. In afurther embodiment, at least one R₁₁ is methyl, ethyl, propyl, i-propyl,butyl, i-butyl, t-butyl, pentyl, or hexyl, each of which is optionallysubstituted with halogen (e.g., F, Cl, Br, or I). In one embodiment,each R₂₈ is independently methyl, ethyl, or propyl. In one embodiment,each R₂₈ is methyl.

In one embodiment, n2 is 1.

In one embodiment, at least one R₂₁ is at the para-position of thephenyl. In one embodiment, at least one R₂₁ is unsubstituted orsubstituted straight-chain C₁-C₆ alkoxy or branched C₃-C₆ alkoxy. In afurther embodiment, at least one R₂₁ is methoxy, ethoxy, propoxy,i-propoxy, butoxy, i-butoxy, t-butoxy, pentoxy, or hexyloxy, each ofwhich is optionally substituted with halogen (e.g., F, Cl, Br, or I). Ina further embodiment, at least one R₂₁ is trifluoromethoxy.

In one embodiment, m2 is 1.

In one embodiment, at least one R₂₂ is unsubstituted or substitutedstraight-chain C₁-C₆ alkyl or branched C₃-C₆ alkyl. In a furtherembodiment, at least one R₂₂ is methyl, ethyl, propyl, i-propyl, butyl,i-butyl, t-butyl, pentyl, or hexyl, each of which is optionallysubstituted with halogen (e.g., F, Cl, Br, or I). In one embodiment, atleast one R₂₂ is methyl.

Any of Z₃, R, R₂₁, R₂₂, R₂₈, n2, m2, o2, and p2 can be selected from anyof the groups described above and combined with any of the groupsdescribed above for one or more of the remainder of Z₃, R, R₂₁, R₂₂,R₂₈, n2, m2, o2, and p2.

In one embodiment, a compound of formula A is a compound of formula III:

or a pharmaceutically acceptable salt thereof, wherein:

Z₁-Z₂ is C(O)—O, O—C(O), C(O)—S, S—C(O), C(O)—NR—NR, or NR—NR—C(O);

each R is independently H or C₁-C₃ alkyl;

R₃₁ is H or unsubstituted or substituted C₁-C₆ alkyl;

n3 is 0, 1, 2, 3, 4, or 5;

each R₃₂ is independently halogen, cyano, unsubstituted or substitutedC₁-C₆ alkyl, unsubstituted or substituted C₁-C₆ alkoxy, orS(O)_(m)3-(unsubstituted or substituted C₁-C₆ alkyl); and

m3 is 0, 1, or 2.

In one embodiment, Z₁-Z₂ is C(O)—O, O—C(O), C(O)—S, or S—C(O).

In one embodiment, Z₁-Z₂ is C(O)—S, S—C(O), C(O)—NR—NR, or NR—NR—C(O).

In one embodiment, Z₁-Z₂ is C(O)—O or O—C(O).

In one embodiment, Z₁-Z₂ is C(O)—O.

In one embodiment, Z₁-Z₂ is C(O)—S or S—C(O).

In one embodiment, Z₁-Z₂ is C(O)—S.

In one embodiment, Z₁-Z₂ is C(O)—NR—NR or NR—NR—C(O).

In one embodiment, Z₁-Z₂ is C(O)—NR—NR.

In one embodiment, each R is H (i.e., Z₁-Z₂ is C(O)—NH—NH orNH—NH—C(O)).

In one embodiment, one of R is H, and the other R is C₁-C₃ alkyl (e.g.,methyl, ethyl, or propyl).

In one embodiment, each R is C₁-C₃ alkyl (e.g., methyl, ethyl, orpropyl).

In one embodiment, R₃₁ is H.

In one embodiment, R₃₁ is unsubstituted or substituted straight-chainC₁-C₆ alkyl or branched C₃-C₆ alkyl. In a further embodiment, R₃₁ ismethyl, ethyl, propyl, i-propyl, butyl, i-butyl, t-butyl, pentyl, orhexyl, each of which is optionally substituted with halogen (e.g., F,Cl, Br, or I). In a further embodiment, R₃₁ is methyl, ethyl, or propyl.In a further embodiment, R₃₁ is methyl.

In one embodiment, n3 is 0, 1, or 2.

In one embodiment, n3 is 0.

In one embodiment, n3 is 1.

In one embodiment, n3 is 2.

In one embodiment, n3 is 3.

In one embodiment, n3 is 4.

In one embodiment, n3 is 5.

In one embodiment, at least one R₃₂ is halogen (e.g., F, Cl, Br, or I).

In one embodiment, at least one R₃₂ is cyano.

In one embodiment, at least one R₃₂ is unsubstituted or substitutedstraight-chain C₁-C₆ alkyl or branched C₃-C₆ alkyl. In a furtherembodiment, at least one R₃₂ is methyl, ethyl, propyl, i-propyl, butyl,i-butyl, t-butyl, pentyl, or hexyl, each of which is optionallysubstituted with halogen (e.g., F, Cl, Br, or I). In a furtherembodiment, at least one R₃₂ is methyl, ethyl, or propyl. In a furtherembodiment, at least one R₃₂ is methyl optionally substituted with oneor more halogen (e.g., F, Cl, Br, or I). In a further embodiment, atleast one R₃₂ is methyl substituted with one or more F. In a furtherembodiment, at least one R₃₂ is CF₃.

In one embodiment, at least one R₃₂ is unsubstituted or substitutedstraight-chain C₁-C₆ alkoxy or branched C₃-C₆ alkoxy. In a furtherembodiment, at least one R₃₂ is methoxy, ethoxy, propoxy, i-propoxy,butoxy, i-butoxy, t-butoxy, pentoxy, or hexyloxy, each of which isoptionally substituted with halogen (e.g., F, Cl, Br, or I).

In one embodiment, at least one R₃₂ is S(O)_(m3)-(unsubstituted orsubstituted C₁-C₆ alkyl). In a further embodiment, at least one R₃₂ isS-(unsubstituted or substituted C₁-C₆ alkyl). In another furtherembodiment, at least one R₃₂ is S(O)-(unsubstituted or substituted C₁-C₆alkyl). In another further embodiment, at least one R₃₂ isS(O)₂-(unsubstituted or substituted C₁-C₆ alkyl). In a furtherembodiment, the unsubstituted or substituted C₁-C₆ alkyl is selectedfrom methyl, ethyl, propyl, i-propyl, butyl, i-butyl, t-butyl, pentyl,and hexyl, each of which is optionally substituted with halogen (e.g.,F, Cl, Br, or I).

In one embodiment, m3 is 0.

In one embodiment, m3 is 1.

In one embodiment, m3 is 2.

Any of the groups described above for any of Z₁, Z₂, R, R₃₁, R₃₂, n3,and m3 can be combined with any of the groups described above for one ormore of the remainder of Z₁, Z₂, R, R₃₁, R₃₂, n3, and m3.

In one embodiment, Z₁-Z₂ is C(O)—O or O—C(O); R₃₁ is unsubstituted orsubstituted straight-chain C₁-C₆ alkyl or branched C₃-C₆ alkyl; and n3is 1 or 2. In a further embodiment, n3 is 2; one R₃₂ is halogen (e.g.,F, Cl, Br, or I) and the other R₃₂ is unsubstituted or substitutedstraight-chain C₁-C₆ alkyl or branched C₃-C₆ alkyl. In a furtherembodiment, one R₃₂ is halogen (e.g., F, Cl, Br, or I) and the other R₃₂is methyl optionally substituted with one or more halogen (e.g., F, Cl,Br, or I). In a further embodiment, one R₃₂ is F and the other R₃₂ isCF₃.

In one embodiment, Z₁-Z₂ is C(O)—O; R₃₁ is unsubstituted or substitutedstraight-chain C₁-C₆ alkyl or branched C₃-C₆ alkyl; and n3 is 1 or 2. Ina further embodiment, n3 is 2; one R₃₂ is halogen (e.g., F, Cl, Br, orI) and the other R₃₂ is unsubstituted or substituted straight-chainC₁-C₆ alkyl or branched C₃-C₆ alkyl. In a further embodiment, one R₃₂ ishalogen (e.g., F, Cl, Br, or I) and the other R₃₂ is methyl optionallysubstituted with one or more halogen (e.g., F, Cl, Br, or I). In afurther embodiment, one R₃₂ is F and the other R₃₂ is CF₃.

In one embodiment, Z₁-Z₂ is C(O)—S or S—C(O); R₃₁ is unsubstituted orsubstituted straight-chain C₁-C₆ alkyl or branched C₃-C₆ alkyl; and n3is 1 or 2. In a further embodiment, n3 is 2; one R₃₂ is halogen (e.g.,F, Cl, Br, or I) and the other R₃₂ is unsubstituted or substitutedstraight-chain C₁-C₆ alkyl or branched C₃-C₆ alkyl. In a furtherembodiment, one R₃₂ is halogen (e.g., F, Cl, Br, or I) and the other R₃₂is methyl optionally substituted with one or more halogen (e.g., F, Cl,Br, or I). In a further embodiment, one R₃₂ is F and the other R₃₂ isCF₃.

In one embodiment, Z₁-Z₂ is C(O)—S; R₃₁ is unsubstituted or substitutedstraight-chain C₁-C₆ alkyl or branched C₃-C₆ alkyl; and n3 is 1 or 2. Ina further embodiment, n3 is 2; one R₃₂ is halogen (e.g., F, Cl, Br, orI) and the other R₃₂ is unsubstituted or substituted straight-chainC₁-C₆ alkyl or branched C₃-C₆ alkyl. In a further embodiment, one R₃₂ ishalogen (e.g., F, Cl, Br, or I) and the other R₃₂ is methyl optionallysubstituted with one or more halogen (e.g., F, Cl, Br, or I). In afurther embodiment, one R₃₂ is F and the other R₃₂ is CF₃.

In one embodiment, Z₁-Z₂ is C(O)—NH—NH or NH—NH—C(O); R₃₁ isunsubstituted or substituted straight-chain C₁-C₆ alkyl or branchedC₃-C₆ alkyl; and n3 is 1 or 2. In a further embodiment, n3 is 2; one R₃₂is halogen (e.g., F, Cl, Br, or I) and the other R₃₂ is unsubstituted orsubstituted straight-chain C₁-C₆ alkyl or branched C₃-C₆ alkyl. In afurther embodiment, one R₃₂ is halogen (e.g., F, Cl, Br, or I) and theother R₃₂ is methyl optionally substituted with one or more halogen(e.g., F, Cl, Br, or I). In a further embodiment, one R₃₂ is F and theother R₃₂ is CF₃.

In one embodiment, Z₁-Z₂ is C(O)—NH—NH; R₃₁ is unsubstituted orsubstituted straight-chain C₁-C₆ alkyl or branched C₃-C₆ alkyl; and n3is 1 or 2. In a further embodiment, n3 is 2; one R₃₂ is halogen (e.g.,F, Cl, Br, or I) and the other R₃₂ is unsubstituted or substitutedstraight-chain C₁-C₆ alkyl or branched C₃-C₆ alkyl. In a furtherembodiment, one R₃₂ is halogen (e.g., F, Cl, Br, or I) and the other R₃₂is methyl optionally substituted with one or more halogen (e.g., F, Cl,Br, or I). In a further embodiment, one R₃₂ is F and the other R₃₂ isCF₃.

In one embodiment, a compound of formula III is a compound of formulaIIIa:

or a pharmaceutically acceptable salt thereof, wherein Z₃ is O, S, orNR—NR; and R, R₃₂, n3, and m3 are each as defined above in formula III.

In one embodiment, Z₃ is O.

In one embodiment, Z₃ is S.

In one embodiment, Z₃ is NR.

In one embodiment, n3 is 2.

Any of Z₃, R, R₃₂, n3, and m3 can be selected from any of the groupsdescribed above and combined with any of the groups described above forone or more of the remainder of Z₃, R, R₃₂, n3, and m3.

In one embodiment, a compound of formula A is a compound of formula IV:

or a pharmaceutically acceptable salt thereof, wherein:

Z₁-Z₂ is C(O)—O, O—C(O), C(O)—S, S—C(O), C(O)—NR—NR, or NR—NR—C(O);

each R is independently H or C₁-C₃ alkyl;

n4 and p4 are each independently 0, 1, 2, 3, 4, or 5;

m4 and o4 are each independently 0, 1, 2, 3, or 4;

each R₄₁, each R₄₂, and each R₄₃ are independently halogen, OH,unsubstituted or substituted C₁-C₆ alkyl, or unsubstituted orsubstituted C₁-C₆ alkoxy;

each R₄₄ is independently halogen, OH, unsubstituted or substitutedC₁-C₆ alkyl, unsubstituted or substituted C₁-C₆ alkoxy, (CH₂)_(q4)—NH₂,(CH₂)_(q4)—NH—C₁-C₆ alkyl, or (CH₂)_(q4)—N(C₁-C₆ alkyl)₂; and

q₄ is 0, 1, 2, 3, 4, 5, or 6.

In one embodiment, Z₁-Z₂ is C(O)—O, O—C(O), C(O)—S, or S—C(O).

In one embodiment, Z₁-Z₂ is C(O)—S, S—C(O), C(O)—NR—NR, or NR—NR—C(O).

In one embodiment, Z₁-Z₂ is C(O)—O or O—C(O).

In one embodiment, Z₁-Z₂ is C(O)—O.

In one embodiment, Z₁-Z₂ is C(O)—S or S—C(O).

In one embodiment, Z₁-Z₂ is C(O)—S.

In one embodiment, Z₁-Z₂ is C(O)—NR—NR or NR—NR—C(O).

In one embodiment, Z₁-Z₂ is C(O)—NR—NR.

In one embodiment, each R is H (i.e., Z₁-Z₂ is C(O)—NH—NH orNH—NH—C(O)).

In one embodiment, one of R is H, and the other R is C₁-C₃ alkyl (e.g.,methyl, ethyl, or propyl).

In one embodiment, each R is C₁-C₃ alkyl (e.g., methyl, ethyl, orpropyl).

In one embodiment, n4 is 0, 1, or 2.

In one embodiment, n4 is 0.

In one embodiment, n4 is 1.

In one embodiment, n4 is 2.

In one embodiment, n4 is 3.

In one embodiment, n4 is 4.

In one embodiment, n4 is 5.

In one embodiment, at least one R₄₁ is halogen (e.g., F, Cl, Br, or I).

In one embodiment, at least one R₄₁ is OH.

In one embodiment, at least one R₄₁ is unsubstituted or substitutedstraight-chain C₁-C₆ alkyl or branched C₃-C₆ alkyl. In a furtherembodiment, at least one R₄₁ is methyl, ethyl, propyl, i-propyl, butyl,i-butyl, t-butyl, pentyl, or hexyl, each of which is optionallysubstituted with halogen (e.g., F, Cl, Br, or I).

In one embodiment, at least one R₄₁ is unsubstituted or substitutedstraight-chain C₁-C₆ alkoxy or branched C₃-C₆ alkoxy. In a furtherembodiment, at least one R₄₁ is methoxy, ethoxy, propoxy, i-propoxy,butoxy, i-butoxy, t-butoxy, pentoxy, or hexyloxy, each of which isoptionally substituted with halogen (e.g., F, Cl, Br, or I).

In one embodiment, m4 is 0, 1, or 2.

In one embodiment, m4 is 0.

In one embodiment, m4 is 1.

In one embodiment, m4 is 2.

In one embodiment, m4 is 3.

In one embodiment, m4 is 4.

In one embodiment, at least one R₄₂ is halogen (e.g., F, Cl, Br, or I).

In one embodiment, at least one R₄₂ is OH.

In one embodiment, at least one R₄₂ is unsubstituted or substitutedstraight-chain C₁-C₆ alkyl or branched C₃-C₆ alkyl. In a furtherembodiment, at least one R₄₂ is methyl, ethyl, propyl, i-propyl, butyl,i-butyl, t-butyl, pentyl, or hexyl, each of which is optionallysubstituted with halogen (e.g., F, Cl, Br, or I).

In one embodiment, at least one R₄₂ is unsubstituted or substitutedstraight-chain C₁-C₆ alkoxy or branched C₃-C₆ alkoxy. In a furtherembodiment, at least one R₄₂ is methoxy, ethoxy, propoxy, i-propoxy,butoxy, i-butoxy, t-butoxy, pentoxy, or hexyloxy, each of which isoptionally substituted with halogen (e.g., F, Cl, Br, or I).

In one embodiment, o4 is 0, 1, or 2.

In one embodiment, o4 is 0.

In one embodiment, o4 is 1.

In one embodiment, o4 is 2.

In one embodiment, o4 is 3.

In one embodiment, o4 is 4.

In one embodiment, at least one R₄₃ is halogen (e.g., F, Cl, Br, or I).

In one embodiment, at least one R₄₃ is OH.

In one embodiment, at least one R₄₃ is unsubstituted or substitutedstraight-chain C₁-C₆ alkyl or branched C₃-C₆ alkyl. In a furtherembodiment, at least one R₄₃ is methyl, ethyl, propyl, i-propyl, butyl,i-butyl, t-butyl, pentyl, or hexyl, each of which is optionallysubstituted with halogen (e.g., F, Cl, Br, or I).

In one embodiment, at least one R₄₃ is unsubstituted or substitutedstraight-chain C₁-C₆ alkoxy or branched C₃-C₆ alkoxy. In a furtherembodiment, at least one R₄₃ is methoxy, ethoxy, propoxy, i-propoxy,butoxy, i-butoxy, t-butoxy, pentoxy, or hexyloxy, each of which isoptionally substituted with halogen (e.g., F, Cl, Br, or I).

In one embodiment, p4 is 0, 1, or 2.

In one embodiment, p4 is 0.

In one embodiment, p4 is 1.

In one embodiment, p4 is 2.

In one embodiment, p4 is 3.

In one embodiment, p4 is 4.

In one embodiment, p4 is 5.

In one embodiment, at least one R₄₄ is halogen (e.g., F, Cl, Br, or I).

In one embodiment, at least one R₄₄ is OH.

In one embodiment, at least one R₄₄ is unsubstituted or substitutedstraight-chain C₁-C₆ alkyl or branched C₃-C₆ alkyl. In a furtherembodiment, at least one R₄₄ is methyl, ethyl, propyl, i-propyl, butyl,i-butyl, t-butyl, pentyl, or hexyl, each of which is optionallysubstituted with halogen (e.g., F, Cl, Br, or I). In a furtherembodiment, at least one R₄₄ is methyl

In one embodiment, at least one R₄₄ is unsubstituted or substitutedstraight-chain C₁-C₆ alkoxy or branched C₃-C₆ alkoxy. In a furtherembodiment, at least one R₄₄ is methoxy, ethoxy, propoxy, i-propoxy,butoxy, i-butoxy, t-butoxy, pentoxy, or hexyloxy, each of which isoptionally substituted with halogen (e.g., F, Cl, Br, or I).

In one embodiment, at least one R₄₄ is (CH₂)_(q4)—NH₂,(CH₂)_(q4)—NH—C₁-C₆ alkyl, or (CH₂)_(q4)—N(C₁-C₆ alkyl)₂, wherein theC₁-C₆ alkyl is methyl, ethyl, propyl, i-propyl, butyl, i-butyl, t-butyl,pentyl, or hexyl, each of which is optionally substituted with halogen(e.g., F, Cl, Br, or I). In a further embodiment, at least one R₄₄ is(CH₂)_(q4)—NH—C₁-C₆ alkyl.

In one embodiment, q4 is 0, 1, 2, or 3.

In one embodiment, q4 is 0.

In one embodiment, q4 is 1.

In one embodiment, q4 is 2.

In one embodiment, q4 is 3.

In one embodiment, q4 is 4.

In one embodiment, q4 is 5.

In one embodiment, q4 is 6.

Any of the groups described above for any of Z₁, Z₂, R, R₄₁, R₄₂, R₄₃,R₄₄, n4, m4, o4, p4, and q4 can be combined with any of the groupsdescribed above for one or more of the remainder of Z₁, Z₂, R, R₄₁, R₄₂,R₄₃, R₄₄, n4, m4, o4, p4, and q4.

In one embodiment, Z₁-Z₂ is C(O)—O or O—C(O); n4, m4, and o4 are each 0;and p4 is 0, 1, or 2. In a further embodiment, p4 is 2.

In one embodiment, Z₁-Z₂ is C(O)—O; n4, m4, and o4 are each 0; and p4 is0, 1, or 2. In a further embodiment, p4 is 2.

In one embodiment, Z₁-Z₂ is C(O)—S or S—C(O); n4, m4, and o4 are each 0;and p4 is 0, 1, or 2. In a further embodiment, p4 is 2.

In one embodiment, Z₁-Z₂ is C(O)—S; n4, m4, and o4 are each 0; and p4 is0, 1, or 2. In a further embodiment, p4 is 2.

In one embodiment, Z₁-Z₂ is C(O)—NH—NH or NH—NH—C(O); n4, m4, and o4 areeach 0; and p4 is 0, 1, or 2. In a further embodiment, p4 is 2.

In one embodiment, Z₁-Z₂ is C(O)—NH; n4, m4, and o4 are each 0; and p4is 0, 1, or 2. In a further embodiment, p4 is 2.

In one embodiment, a compound of formula A is a compound of formula V:

or a pharmaceutically acceptable salt thereof, wherein:

Z₁-Z₂ is C(O)—O, O—C(O), C(O)—S, S—C(O), C(O)—NR—NR, or NR—NR—C(O);

each R is independently H or C₁-C₃ alkyl;

A₁, A₃, A₄, A₅, A₆, and A₈ are each independently N, NR₅₃, or CR₅₃;

A₂ and A₇ are each independently N or C;

each R₅₃ is independently H, halogen, OH, unsubstituted or substitutedC₁-C₆ alkyl, or unsubstituted or substituted C₁-C₆ alkoxy;

n5 is 0, 1, 2, 3, or 4;

each R₅₁ is independently halogen, OH, unsubstituted or substitutedC₁-C₆ alkyl, or unsubstituted or substituted C₁-C₆ alkoxy;

m5 is 0, 1, 2, 3, 4, or 5; and

each R₅₂ is independently halogen, OH, unsubstituted or substitutedC₁-C₆ alkyl, or unsubstituted or substituted C₁-C₆ alkoxy.

In one embodiment, Z₁-Z₂ is C(O)—O, O—C(O), C(O)—S, or S—C(O).

In one embodiment, Z₁-Z₂ is C(O)—S, S—C(O), C(O)—NR—NR, or NR—NR—C(O).

In one embodiment, Z₁-Z₂ is C(O)—O or O—C(O).

In one embodiment, Z₁-Z₂ is C(O)—O.

In one embodiment, Z₁-Z₂ is C(O)—S or S—C(O).

In one embodiment, Z₁-Z₂ is C(O)—S.

In one embodiment, Z₁-Z₂ is C(O)—NR—NR or NR—NR—C(O).

In one embodiment, Z₁-Z₂ is C(O)—NR—NR.

In one embodiment, each R is H (i.e., Z₁-Z₂ is C(O)—NH—NH orNH—NH—C(O)).

In one embodiment, one of R is H, and the other R is C₁-C₃ alkyl (e.g.,methyl, ethyl, or propyl).

In one embodiment, each R is C₁-C₃ alkyl (e.g., methyl, ethyl, orpropyl).

In one embodiment, A₁, A₃, A₄, A₅, A₆, and A₈ are each CR₅₃.

In one embodiment, one of A₁, A₃, A₄, A₅, A₆, and A₈ is N or NR₅₃, andthe remainder of A₁, A₃, A₄, A₅, A₆, and A₈ are CR₅₃.

In one embodiment, two of A₁, A₃, A₄, A₅, A₆, and A₈ are N or NR₅₃, andthe remainder of A₁, A₃, A₄, A₅, A₆, and A₈ are CR₅₃.

In one embodiment, three of A₁, A₃, A₄, A₅, A₆, and A₈ are N or NR₅₃,and the remainder of A₁, A₃, A₄, A₅, A₆, and A₈ are CR₅₃.

In one embodiment, four of A₁, A₃, A₄, A₅, A₆, and A₈ are N or NR₅₃, andthe remainder of A₁, A₃, A₄, A₅, A₆, and A₈ are CR₅₃.

In one embodiment, five of A₁, A₃, A₄, A₅, A₆, and A₈ are N or NR₅₃, andthe remainder of A₁, A₃, A₄, A₅, A₆, and A₈ is CR₅₃.

In one embodiment, A₂ and A₇ are each N.

In one embodiment, one of A₂ and A₇ is N, and the other is C.

In one embodiment, A₂ and A₇ are each C.

In one embodiment, at least one R₅₃ is halogen (e.g., F, Cl, Br, or I).

In one embodiment, at least one R₅₃ is OH.

In one embodiment, at least one R₅₃ is unsubstituted or substitutedstraight-chain C₁-C₆ alkyl or branched C₃-C₆ alkyl. In a furtherembodiment, at least one R₅₃ is methyl, ethyl, propyl, i-propyl, butyl,i-butyl, t-butyl, pentyl, or hexyl, each of which is optionallysubstituted with halogen (e.g., F, Cl, Br, or I).

In one embodiment, at least one R₅₃ is unsubstituted or substitutedstraight-chain C₁-C₆ alkoxy or branched C₃-C₆ alkoxy. In a furtherembodiment, at least one R₅₃ is methoxy, ethoxy, propoxy, i-propoxy,butoxy, i-butoxy, t-butoxy, pentoxy, or hexyloxy, each of which isoptionally substituted with halogen (e.g., F, Cl, Br, or I).

In one embodiment, n5 is 0, 1, or 2.

In one embodiment, n5 is 0.

In one embodiment, n5 is 1.

In one embodiment, n5 is 2.

In one embodiment, n5 is 3.

In one embodiment, n5 is 4.

In one embodiment, at least one R₅₁ is halogen (e.g., F, Cl, Br, or I).

In one embodiment, at least one R₅₁ is OH.

In one embodiment, at least one R₅₁ is unsubstituted or substitutedstraight-chain C₁-C₆ alkyl or branched C₃-C₆ alkyl. In a furtherembodiment, at least one R₅₁ is methyl, ethyl, propyl, i-propyl, butyl,i-butyl, t-butyl, pentyl, or hexyl, each of which is optionallysubstituted with halogen (e.g., F, Cl, Br, or I).

In one embodiment, at least one R₅₁ is unsubstituted or substitutedstraight-chain C₁-C₆ alkoxy or branched C₃-C₆ alkoxy. In a furtherembodiment, at least one R₅₁ is methoxy, ethoxy, propoxy, i-propoxy,butoxy, i-butoxy, t-butoxy, pentoxy, or hexyloxy, each of which isoptionally substituted with halogen (e.g., F, Cl, Br, or I).

In one embodiment, m5 is 0, 1, or 2.

In one embodiment, m5 is 0.

In one embodiment, m5 is 1.

In one embodiment, m5 is 2.

In one embodiment, m5 is 3.

In one embodiment, m5 is 4.

In one embodiment, m5 is 5.

In one embodiment, at least one R₅₂ is halogen (e.g., F, Cl, Br, or I).

In one embodiment, at least one R₅₂ is OH.

In one embodiment, at least one R₅₂ is unsubstituted or substitutedstraight-chain C₁-C₆ alkyl or branched C₃-C₆ alkyl. In a furtherembodiment, at least one R₅₂ is methyl, ethyl, propyl, i-propyl, butyl,i-butyl, t-butyl, pentyl, or hexyl, each of which is optionallysubstituted with halogen (e.g., F, Cl, Br, or I).

In one embodiment, at least one R₅₂ is unsubstituted or substitutedstraight-chain C₁-C₆ alkoxy or branched C₃-C₆ alkoxy. In a furtherembodiment, at least one R₅₂ is methoxy, ethoxy, propoxy, i-propoxy,butoxy, i-butoxy, t-butoxy, pentoxy, or hexyloxy, each of which isoptionally substituted with halogen (e.g., F, Cl, Br, or I).

Any of the groups described above for any of Z₁, Z₂, R, A₁, A₂, A₃, A₄,A₅, A₆, A₇, As, R₅₁, R₅₂, R₅₃, n5, and m5 can be combined with any ofthe groups described above for one or more of the remainder of Z₁, Z₂,R, A₁, A₂, A₃, A₄, A₅, A₆, A₇, A₈, R₅₁, R₅₂, R₅₃, n5, and m5.

In one embodiment, a compound of formula V is a compound of formula Va:

or a pharmaceutically acceptable salt thereof, wherein:

Z₃ is O, S, or NR—NR;

o5 is 0, 1, 2, 3, 4, or 5; and

R, R₅₁, R₅₂, R₅₃, n5, and m5 are each as defined above in formula V.

In one embodiment, Z₃ is O.

In one embodiment, Z₃ is S.

In one embodiment, Z₃ is NR.

In one embodiment, o5 is 0, 1, or 2.

In one embodiment, o5 is 0.

In one embodiment, o5 is 1.

In one embodiment, o5 is 2.

In one embodiment, o5 is 3.

In one embodiment, o5 is 4.

In one embodiment, o5 is 5.

In one embodiment, n5 is 0 or 1.

In one embodiment, m5 is 0 or 1.

Any of Z₃, R, R₅₁, R₅₂, R₅₃, n5, m5, and o5 can be selected from any ofthe groups described above and combined with any of the groups describedabove for one or more of the remainder of Z₃, R, R₅₁, R₅₂, R₅₃, n5, m5,and o5.

The present application provides a compound of a compound of formula(VI):

or a pharmaceutically acceptable salt thereof, wherein:

Za and Zb are each independently 0 or NR, wherein at least one of Za andZb is 0;

R is H or C₁-C₃ alkyl;

n6 is 0, 1, 2, 3, 4, or 5;

each R₆₁ is independently halogen, cyano, OH, unsubstituted orsubstituted C₁-C₆ alkyl, or unsubstituted or substituted C₁-C₆ alkoxy;

R₆₂ is unsubstituted or substituted C₁-C₆ alkyl;

m6 is 0, 1, 2, 3, or 4; and

each R₆₃ is independently halogen, cyano, OH, unsubstituted orsubstituted C₁-C₆ alkyl, unsubstituted or substituted C₁-C₆ alkoxy,unsubstituted or substituted C₃-C₈ cycloalkyl, unsubstituted orsubstituted C₆-C₁₀ aryl, unsubstituted or substituted heterocyclylcomprising one or two 5- to 8-membered rings and 1-4 heteroatomsselected from O, N, and S, or unsubstituted or substituted heteroarylcomprising one or two 5- to 8-membered rings and 1-4 heteroatomsselected from O, N, and S.

In one embodiment, Za is O and Zb is NR.

In one embodiment, Za is NR and Zb is O

In one embodiment, Za is O and Zb is O.

In one embodiment, R is H.

In one embodiment, R is C₁-C₃ alkyl (e.g., methyl, ethyl, or propyl).

In one embodiment, n6 is 0, 1, or 2.

In one embodiment, n6 is 0.

In one embodiment, n6 is 1.

In one embodiment, n6 is 2.

In one embodiment, n6 is 3.

In one embodiment, n6 is 4.

In one embodiment, n6 is 5.

In one embodiment, at least one R₆₁ is halogen (e.g., F, Cl, Br, or I).

In one embodiment, at least one R₆₁ is cyano.

In one embodiment, at least one R₆₁ is OH.

In one embodiment, at least one R₆₁ is unsubstituted or substitutedstraight-chain C₁-C₆ alkyl or branched C₃-C₆ alkyl. In a furtherembodiment, at least one R₆₁ is methyl, ethyl, propyl, i-propyl, butyl,i-butyl, t-butyl, pentyl, or hexyl, each of which is optionallysubstituted with halogen (e.g., F, Cl, Br, or I).

In one embodiment, at least one R₆₁ is unsubstituted or substitutedstraight-chain C₁-C₆ alkoxy or branched C₃-C₆ alkoxy. In a furtherembodiment, at least one R₆₁ is methoxy, ethoxy, propoxy, i-propoxy,butoxy, i-butoxy, t-butoxy, pentoxy, or hexyloxy, each of which isoptionally substituted with halogen (e.g., F, Cl, Br, or I).

In one embodiment, R₆₂ is unsubstituted or substituted straight-chainC₁-C₆ alkyl or branched C₃-C₆ alkyl. In a further embodiment, R₆₂ ismethyl, ethyl, propyl, i-propyl, butyl, i-butyl, t-butyl, pentyl, orhexyl, each of which is optionally substituted with halogen (e.g., F,Cl, Br, or I).

In one embodiment, m6 is 0, 1, or 2.

In one embodiment, m6 is 0.

In one embodiment, m6 is 1.

In one embodiment, m6 is 2.

In one embodiment, m6 is 3.

In one embodiment, m6 is 4.

In one embodiment, at least one R₆₃ is halogen (e.g., F, Cl, Br, or I),cyano, OH, unsubstituted or substituted C₁-C₆ alkyl, or unsubstituted orsubstituted C₁-C₆ alkoxy.

In one embodiment, at least one R₆₃ is halogen (e.g., F, Cl, Br, or I).

In one embodiment, at least one R₆₃ is cyano.

In one embodiment, at least one R₆₃ is OH.

In one embodiment, at least one R₆₃ is unsubstituted or substitutedstraight-chain C₁-C₆ alkyl or branched C₃-C₆ alkyl. In a furtherembodiment, at least one R₆₃ is methyl, ethyl, propyl, i-propyl, butyl,i-butyl, t-butyl, pentyl, or hexyl, each of which is optionallysubstituted with halogen (e.g., F, Cl, Br, or I).

In one embodiment, at least one R₆₃ is unsubstituted or substitutedstraight-chain C₁-C₆ alkoxy or branched C₃-C₆ alkoxy. In a furtherembodiment, at least one R₆₃ is methoxy, ethoxy, propoxy, i-propoxy,butoxy, i-butoxy, t-butoxy, pentoxy, or hexyloxy, each of which isoptionally substituted with halogen (e.g., F, Cl, Br, or I).

In one embodiment, at least one R₆₃ is unsubstituted or substitutedC₃-C₈ cycloalkyl, unsubstituted or substituted C₆-C₁₀ aryl,unsubstituted or substituted heterocyclyl comprising one or two 5- to8-membered rings and 1-4 heteroatoms selected from O, N, and S, orunsubstituted or substituted heteroaryl comprising one or two 5- to8-membered rings and 1-4 heteroatoms selected from O, N, and S.

In one embodiment, at least one R₆₃ is C₃-C₈ cycloalkyl selected fromcyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, andcyclooctyl, each of which is optionally substituted with one or moresubstituents independently selected from halogen, OH, cyano, nitro,C₁-C₆ alkyl, C₁-C₆ alkoxy, and amino.

In one embodiment, at least one R₆₃ is phenyl optionally substitutedwith one or more substituents independently selected from halogen, OH,cyano, nitro, C₁-C₆ alkyl, C₁-C₆ alkoxy, and amino.

In one embodiment, at least one R₆₃ is heterocyclyl optionallysubstituted with one or more substituents independently selected fromhalogen, OH, cyano, nitro, C₁-C₆ alkyl, C₁-C₆ alkoxy, and amino. In afurther embodiment, at least one R₆₃ is heterocyclyl comprising a 5- or6-membered ring optionally substituted with one or more substituentsindependently selected from halogen, OH, cyano, nitro, C₁-C₆ alkyl,C₁-C₆ alkoxy, and amino.

In one embodiment, at least one R₆₃ is heteroaryl optionally substitutedwith one or more substituents independently selected from halogen, OH,cyano, nitro, C₁-C₆ alkyl, C₁-C₆ alkoxy, and amino. In a furtherembodiment, at least one R₆₃ is heteroaryl selected from pyrrolyl,imidazolyl, pyrazolyl, pyridinyl, pyrimidinyl, indolyl, andbenzoimidazolyl, each of which is optionally substituted with one ormore substituents independently selected from halogen, OH, cyano, nitro,C₁-C₆ alkyl, C₁-C₆ alkoxy, and amino. In a further embodiment, at leastone R₆₃ is benzoimidazolyl.

Any of the groups described above for any of Za, Zb, R, R₆₁, R₆₂, R₆₃,n6, and m6 can be combined with any of the groups described above forone or more of the remainder of Za, Zb, R, R₆₁, R₆₂, R₆₃, n6, and m6.

In one embodiment, Za is O and Zb is NH; n6 is 0 or 1; m6 is 0 or 1; andR₆₃ is unsubstituted or substituted C₃-C₈ cycloalkyl, unsubstituted orsubstituted C₆-C₁₀ aryl, unsubstituted or substituted heterocyclylcomprising one or two 5- to 8-membered rings and 1-4 heteroatomsselected from O, N, and S, or unsubstituted or substituted heteroarylcomprising one or two 5- to 8-membered rings and 1-4 heteroatomsselected from O, N, and S. In a further embodiment, R₆₂ is methyl. In afurther embodiment, at least one R₆₃ is unsubstituted or substitutedheteroaryl comprising one or two 5- to 8-membered rings and 1-4heteroatoms selected from O, N, and S. In a further embodiment, at leastone R₆₃ is benzoimidazolyl. In a further embodiment, at least one R₆₃ isbenzoimidazolyl. In a further embodiment, at least one R₆₁ is cyano.

In one embodiment, Za is NH and Zb is O; n6 is 0 or 1; m6 is 0 or 1; andR₆₃ is unsubstituted or substituted C₃-C₈ cycloalkyl, unsubstituted orsubstituted C₆-C₁₀ aryl, unsubstituted or substituted heterocyclylcomprising one or two 5- to 8-membered rings and 1-4 heteroatomsselected from O, N, and S, or unsubstituted or substituted heteroarylcomprising one or two 5- to 8-membered rings and 1-4 heteroatomsselected from O, N, and S. In a further embodiment, R₆₂ is methyl. In afurther embodiment, at least one R₆₃ is unsubstituted or substitutedheteroaryl comprising one or two 5- to 8-membered rings and 1-4heteroatoms selected from O, N, and S. In a further embodiment, at leastone R₆₃ is benzoimidazolyl. In a further embodiment, at least one R₆₁ iscyano.

In one embodiment, a compound of formula (VI) is a compound of formula(VIa):

or a pharmaceutically acceptable salt thereof, wherein Za, Zb, R, R₆₁,R₆₃, and n6 are each as defined above in formula (VI).

In one embodiment, n6 is 1.

In one embodiment, at least one R₆₁ is at the para-position of thephenyl ring. In one embodiment, at least one R₆₁ is cyano.

In one embodiment, R₆₃ is heteroaryl optionally substituted with one ormore substituents independently selected from halogen, OH, cyano, nitro,C₁-C₆ alkyl, C₁-C₆ alkoxy, and amino. In a further embodiment, at leastone R₆₃ is heteroaryl selected from pyrrolyl, imidazolyl, pyrazolyl,pyridinyl, pyrimidinyl, indolyl, and benzoimidazolyl, each of which isoptionally substituted with one or more substituents independentlyselected from halogen, OH, cyano, nitro, C₁-C₆ alkyl, C₁-C₆ alkoxy, andamino. In a further embodiment, at least one R₆₃ is benzoimidazolyl.

Any of Za, Zb, R, R₆₁, R₆₃, and n6 can be selected from any of thegroups described above and combined with any of the groups describedabove for one or more of the remainder of Za, Zb, R, R₆₁, R₆₃, and n6.

It will be understood that the above classes may be combined to formadditional classes, as for example the combination of selections of twoor more substituents.

Representative compounds of the present application include compoundslisted in

TABLE 1 Cmpd No. Structure 1-3

4-6

7-9

10-12

13-15

16-18

19-21

22-24

25-27

28-30

31-33

34-36

37

38

As used herein, “alkyl”, “C₁, C₂, C₃, C₄, C₅ or C₆ alkyl” or “C₁-C₆alkyl” is intended to include C₁, C₂, C₃, C₄, C₅ or C₆ straight chain(linear) saturated aliphatic hydrocarbon groups and C₃, C₄, C₅ or C₆branched saturated aliphatic hydrocarbon groups. For example, C₁-C₆alkyl is intended to include Cl, C₂, C₃, C₄, C₅ and C₆ alkyl groups.Examples of alkyl include, moieties having from one to six carbon atoms,such as, but not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl,s-butyl, t-butyl, n-pentyl, s-pentyl and n-hexyl.

In certain embodiments, a straight chain or branched alkyl has six orfewer carbon atoms (e.g., C₁-C₆ for straight chain, C₃-C₆ for branchedchain), and in another embodiment, a straight chain or branched alkylhas four or fewer carbon atoms.

As used herein, the term “cycloalkyl”, “C₃, C₄, C₅, C₆, C₇ or C₈cycloalkyl” or “C₃-C₈ cycloalkyl” is intended to include hydrocarbonrings having from three to eight carbon atoms in their ring structure.In one embodiment, a cycloalkyl group has five or six carbons in thering structure.

The term “substituted alkyl” or “substituted C₁-C₆ alkyl” refers toalkyl moieties having substituents replacing one or more hydrogen atomson one or more carbons of the hydrocarbon backbone. Such substituentscan include, for example, alkyl, cycloalkyl, alkenyl, alkynyl, aryl,heteroaryl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy,alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl,arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl,dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, aryloxyl, phosphate,phosphonato, phosphinato, amino (including NH₂, monoalkylamino e.g.,NH(C₁-C₆)alkyl, dialkylamino e.g., N[(C₁-C₆)alkyl]₂, arylamino,diarylamino and alkylarylamino), acylamino (includingalkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino,imino, sulfhydryl, SH, alkylthio, arylthio, thiocarboxylate, sulfates,alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro,trifluoromethyl, CH₂, F, CHF₂, OCF₃, cyano, azido, heterocyclyl,alkylaryl, or an aromatic or heteroaromatic moiety. Cycloalkyls can befurther substituted, e.g., with the substituents described above.

“Aryl” includes groups with aromaticity, including “conjugated”, ormulticyclic, systems with at least one aromatic ring. Examples includephenyl, napthalene, etc. The term “C₆-C₁₀” includes aryl groupscontaining six to ten carbon atoms.

“Heteroaryl” groups are groups with aromaticity, including “conjugated”,or multicyclic, systems with at least one aromatic ring having from oneto four heteroatoms in the ring structure, and may also be referred toas “aryl heterocycles” or “heteroaromatics”. A heteroaryl group can bepartially aromatic, i.e., not all of the rings are aromatic. As usedherein, the term “heteroaryl” is intended to include a stable 5-, 6-, or7-membered monocyclic or 7-, 8-, 9-, 10-, 11- or 12-membered bicyclicaromatic heterocyclic ring which consists of carbon atoms and one ormore heteroatoms, e.g., 1 or 1-2 or 1, 2, or 3 or 1, 2, 3, or 4 or 1, 2,3, 4, or 5 or 1, 2, 3, 4, 5, or 6 heteroatoms, independently selectedfrom the group consisting of nitrogen, oxygen and sulfur. In one aspect,a heteroaryl comprises one or two 5- or 6-membered rings and 1-4heteroatoms selected from N, O and S. For an “unsubstituted heteroaryl”,the nitrogen atom may be substituted or unsubstituted (i.e., N or NRwherein R is H). The nitrogen and sulfur heteroatoms may optionally beoxidized (i.e., N→O and S(O)_(p), where p=1 or 2). It is to be notedthat total number of S and O atoms in the aromatic heterocycle is notmore than 1.

Examples of heteroaryl groups include pyrrole, furan, thiophene,thiazole, isothiazole, imidazole, triazole, tetrazole, pyrazole,oxazole, isoxazole, pyridine, pyrazine, pyridazine, pyrimidine,quinoline, benzofuran, benzoimidazole, imidazopyridine, thiophene,indole, and the like.

Furthermore, the terms “aryl” and “heteroaryl” include multicyclic aryland heteroaryl groups, e.g., tricyclic, bicyclic, e.g., naphthalene,benzoxazole, benzodioxazole, benzothiazole, benzoimidazole,benzothiophene, methylenedioxyphenyl, quinoline, isoquinoline,naphthridine, indole, benzofuran, purine, benzofuran, deazapurine,indolizine.

In the case of multicyclic aromatic rings, only one of the rings needsto be aromatic (e.g., 2,3-dihydroindole), although all of the rings maybe aromatic (e.g., quinoline). The second ring can also be fused orbridged.

The aryl or heteroaryl aromatic ring can be substituted at one or morering positions with such substituents as described above, for example,alkyl, alkenyl, akynyl, halogen, hydroxyl, alkoxy, alkylcarbonyloxy,arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate,alkylcarbonyl, alkylaminocarbonyl, aralkylaminocarbonyl,alkenylaminocarbonyl, alkylcarbonyl, arylcarbonyl, aralkylcarbonyl,alkenylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylthiocarbonyl,phosphate, phosphonato, phosphinato, amino (including alkylamino,dialkylamino, arylamino, diarylamino and alkylarylamino), acylamino(including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido),amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate,sulfates, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro,trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromaticor heteroaromatic moiety. Aryl groups can also be fused or bridged withalicyclic or heterocyclic rings, which are not aromatic so as to form amulticyclic system (e.g., tetralin, methylenedioxyphenyl).

As used herein, “carbocycle” or “carbocyclic ring” is intended toinclude any stable monocyclic, bicyclic or tricyclic ring having thespecified number of carbons, any of which may be saturated, unsaturated,or aromatic. For example, a C₃-C₁₄ carbocycle is intended to include amonocyclic, bicyclic or tricyclic ring having 3, 4, 5, 6, 7, 8, 9, 10,11, 12, 13 or 14 carbon atoms. Examples of carbocycles include, but arenot limited to, cyclopropyl, cyclobutyl, cyclobutenyl, cyclopentyl,cyclopentenyl, cyclohexyl, cycloheptenyl, cycloheptyl, cycloheptenyl,adamantyl, cyclooctyl, cyclooctenyl, cyclooctadienyl, fluorenyl, phenyl,naphthyl, indanyl, adamantyl and tetrahydronaphthyl. Bridged rings arealso included in the definition of carbocycle, including, for example,[3.3.0]bicyclooctane, [4.3.0]bicyclononane, [4.4.0]bicyclodecane and[2.2.2]bicyclooctane. A bridged ring occurs when one or more carbonatoms link two non-adjacent carbon atoms. In one embodiment, bridgerings are one or two carbon atoms. It is noted that a bridge alwaysconverts a monocyclic ring into a tricyclic ring. When a ring isbridged, the substituents recited for the ring may also be present onthe bridge. Fused (e.g., naphthyl, tetrahydronaphthyl) and spiro ringsare also included.

As used herein, “heterocycle” includes any ring structure (saturated orpartially unsaturated) which contains at least one ring heteroatom(e.g., N, O or S). In one aspect, a heterocycle comprises one, two, orthree 5- or 6-membered saturated rings and 1-4 heteroatoms selected fromN, O and S. In another aspect, a heterocycle comprises one, two, orthree 5- or 6-membered partially saturated and/or saturated rings and1-4 heteroatoms selected from N, O and S. In one aspect, a heterocyclecomprises spiro rings. Examples of heterocycles include, but are notlimited to, morpholine, pyrrolidine, tetrahydrothiophene, piperidine,piperazine and tetrahydrofuran.

Additional examples of heterocyclic groups include, but are not limitedto, acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl,benzothiophenyl, benzoxazolyl, benzoxazolinyl, benzthiazolyl,benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl,benzimidazolinyl, carbazolyl, 4aH-carbazolyl, carbolinyl, chromanyl,chromenyl, cinnolinyl, decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl,dihydrofuro[2,3-b]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl,imidazolinyl, imidazolyl, 1H-indazolyl, indolenyl, indolinyl,indolizinyl, indolyl, 3H-indolyl, isatinoyl, isobenzofuranyl,isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl,isothiazolyl, isoxazolyl, methylenedioxyphenyl, morpholinyl,naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl,1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl,1,2,4-oxadiazol5(4H)-one, oxazolidinyl, oxazolyl, oxindolyl,pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl,phenothiazinyl, phenoxathinyl, phenoxazinyl, phthalazinyl, piperazinyl,piperidinyl, piperidonyl, 4-piperidonyl, piperonyl, pteridinyl, purinyl,pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl,pyridooxazole, pyridoimidazole, pyridothiazole, pyridinyl, pyridyl,pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl, pyrrolyl,quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl,tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl,tetrazolyl, 6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl,1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl,thianthrenyl, thiazolyl, thienyl, thienothiazolyl, thienooxazolyl,thienoimidazolyl, thiophenyl, triazinyl, 1,2,3-triazolyl,1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl and xanthenyl.

The term “substituted”, as used herein, means that any one or morehydrogen atoms on the designated atom is replaced with a selection fromthe indicated groups, provided that the designated atom's normal valencyis not exceeded, and that the substitution results in a stable compound.When a substituent is keto (i.e., ═O), then 2 hydrogen atoms on the atomare replaced. Keto substituents are not present on aromatic moieties.Ring double bonds, as used herein, are double bonds that are formedbetween two adjacent ring atoms (e.g., C═C, C═N or N═N). “Stablecompound” and “stable structure” are meant to indicate a compound thatis sufficiently robust to survive isolation to a useful degree of purityfrom a reaction mixture, and formulation into an efficacious therapeuticagent.

When a bond to a substituent is shown to cross a bond connecting twoatoms in a ring, then such substituent may be bonded to any atom in thering. When a substituent is listed without indicating the atom via whichsuch substituent is bonded to the rest of the compound of a givenformula, then such substituent may be bonded via any atom in suchformula. Combinations of substituents and/or variables are permissible,but only if such combinations result in stable compounds.

When any variable (e.g., R₄) occurs more than one time in anyconstituent or formula for a compound, its definition at each occurrenceis independent of its definition at every other occurrence. Thus, forexample, if a group is shown to be substituted with 0-2 R₄ moieties,then the group may optionally be substituted with up to two R₄ moietiesand R₄ at each occurrence is selected independently from the definitionof R₄. Also, combinations of substituents and/or variables arepermissible, but only if such combinations result in stable compounds.

The term “hydroxy” or “hydroxyl” includes groups with an —OH or —O⁻.

As used herein, “halo” or “halogen” refers to fluoro, chloro, bromo andiodo. The term “perhalogenated” generally refers to a moiety wherein allhydrogen atoms are replaced by halogen atoms.

The term “carbonyl” or “carboxy” includes compounds and moieties whichcontain a carbon connected with a double bond to an oxygen atom.Examples of moieties containing a carbonyl include, but are not limitedto, aldehydes, ketones, carboxylic acids, amides, esters, anhydrides,etc.

“Acyl” includes moieties that contain the acyl radical (—C(O)—) or acarbonyl group. “Substituted acyl” includes acyl groups where one ormore of the hydrogen atoms are replaced by, for example, alkyl groups,alkynyl groups, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy,alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl,arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl,dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate,phosphonato, phosphinato, amino (including alkylamino, dialkylamino,arylamino, diarylamino and alkylarylamino), acylamino (includingalkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino,imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates,alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro,trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromaticor heteroaromatic moiety.

The term “alkoxy” or “alkoxyl” includes substituted and unsubstitutedalkyl, alkenyl and alkynyl groups covalently linked to an oxygen atom.“C₁-C₆ alkoxy” includes alkoxy groups with an alkyl group having one,two, three, four, five, or six carbon atoms. Examples of alkoxy groupsor alkoxyl radicals include, but are not limited to, methoxy, ethoxy,isopropyloxy, propoxy, butoxy and pentoxy groups. Examples ofsubstituted alkoxy groups include halogenated alkoxy groups. The alkoxygroups can be substituted with groups such as alkenyl, alkynyl, halogen,hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy,aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl,alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl,alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, amino(including alkylamino, dialkylamino, arylamino, diarylamino, andalkylarylamino), acylamino (including alkylcarbonylamino,arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl,alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl,sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido,heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moieties.Examples of halogen substituted alkoxy groups include, but are notlimited to, fluoromethoxy, difluoromethoxy, trifluoromethoxy,chloromethoxy, dichloromethoxy and trichloromethoxy.

The term “ester” includes compounds or moieties which contain a carbonbound to an oxygen atom which is bonded to the carbon of a carbonylgroup. The term “ester” includes alkoxycarboxy groups such asmethoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl,pentoxycarbonyl, etc.

The term “thioester” includes compounds or moieties which contain acarbon bound to a sulfur atom which is bonded to the carbon of acarbonyl group.

As used herein, “amine” or “amino” or “NH₂” includes moieties where anitrogen atom is covalently bonded to at least one carbon or heteroatom.“Alkylamino” or “monoalkylamino” includes groups of compounds whereinnitrogen is bound to at least one alkyl group. “NH(C₁-C₆) alkyl” is analkylamino group having an alkyl group with one, two, three, four, five,or six carbon atoms. Examples of alkylamino groups include benzylamino,methylamino, ethylamino, phenethylamino, etc. “Dialkylamino” includesgroups wherein the nitrogen atom is bound to at least two additionalalkyl groups. “N[(C₁-C₆) alkyl” is a dialkylamino group having two alkylgroups each with one, two, three, four, five, or six carbon atoms. Thetwo alkyl groups are the same or different. Examples of dialkylaminogroups include, but are not limited to, dimethylamino and diethylamino.

The term “amide” or “aminocarboxy” includes compounds or moieties thatcontain a nitrogen atom that is bound to the carbon of a carbonyl or athiocarbonyl group.

Compounds of the present application that contain nitrogens can beconverted to N-oxides by treatment with an oxidizing agent (e.g.,3-chloroperoxybenzoic acid (m-CPBA) and/or hydrogen peroxides) to affordother compounds of the present application. Thus, all shown and claimednitrogen-containing compounds are considered, when allowed by valencyand structure, to include both the compound as shown and its N-oxidederivative (which can be designated as N→O or N⁺—O⁻). Furthermore, inother instances, the nitrogens in the compounds of the presentapplication can be converted to N-hydroxy or N-alkoxy compounds. Forexample, N-hydroxy compounds can be prepared by oxidation of the parentamine by an oxidizing agent such as m-CPBA. All shown and claimednitrogen-containing compounds are also considered, when allowed byvalency and structure, to cover both the compound as shown and itsN-hydroxy (i.e., N—OH) and N-alkoxy (i.e., N—OR, wherein R issubstituted or unsubstituted C₁-C₆ alkyl, C₁-C₆ alkenyl, C₁-C₆ alkynyl,3-14-membered carbocycle or 3-14-membered heterocycle) derivatives.

In the present specification, the structural formula of the compoundrepresents a certain isomer for convenience in some cases, but thepresent application includes all isomers, such as geometrical isomers,optical isomers based on an asymmetrical carbon, stereoisomers,tautomers, and the like. In addition, a crystal polymorphism may bepresent for the compounds represented by the formulae presented herein.It is noted that any crystal form, crystal form mixture, or anhydride orhydrate thereof is included in the scope of the present application.Furthermore, so-called metabolite which is produced by degradation ofthe present compound in vivo is included in the scope of the presentapplication.

“Isomerism” means compounds that have identical molecular formulae butdiffer in the sequence of bonding of their atoms or in the arrangementof their atoms in space. Isomers that differ in the arrangement of theiratoms in space are termed “stereoisomers”. Stereoisomers that are notmirror images of one another are termed “diastereoisomers”, andstereoisomers that are non-superimposable mirror images of each otherare termed “enantiomers” or sometimes optical isomers. A mixturecontaining equal amounts of individual enantiomeric forms of oppositechirality is termed a “racemic mixture”.

A carbon atom bonded to four nonidentical substituents is termed a“chiral center”.

“Chiral isomer” means a compound with at least one chiral center.Compounds with more than one chiral center may exist either as anindividual diastereomer or as a mixture of diastereomers, termed“diastereomeric mixture”. When one chiral center is present, astereoisomer may be characterized by the absolute configuration (R or S)of that chiral center. Absolute configuration refers to the arrangementin space of the substituents attached to the chiral center. Thesubstituents attached to the chiral center under consideration areranked in accordance with the Sequence Rule of Cahn, Ingold and Prelog.(Cahn et al., Angew. Chem. Inter. Edit. 1966, 5, 385; errata 511; Cahnet al., Angew. Chem. 1966, 78, 413; Cahn and Ingold, J. Chem. Soc. 1951(London), 612; Cahn et al., Experientia 1956, 12, 81; Cahn, J. Chem.Educ. 1964, 41, 116).

“Geometric isomer” means the diastereomers that owe their existence tohindered rotation about double bonds. These configurations aredifferentiated in their names by the prefixes cis and trans, or Z and E,which indicate that the groups are on the same or opposite side of thedouble bond in the molecule according to the Cahn-Ingold-Prelog rules.

Furthermore, the structures and other compounds discussed in thisapplication include all atropic isomers thereof “Atropic isomers” are atype of stereoisomer in which the atoms of two isomers are arrangeddifferently in space. Atropic isomers owe their existence to arestricted rotation caused by hindrance of rotation of large groupsabout a central bond. Such atropic isomers typically exist as a mixture,however as a result of recent advances in chromatography techniques; ithas been possible to separate mixtures of two atropic isomers in selectcases.

“Tautomer” is one of two or more structural isomers that exist inequilibrium and is readily converted from one isomeric form to another.This conversion results in the formal migration of a hydrogen atomaccompanied by a switch of adjacent conjugated double bonds. Tautomersexist as a mixture of a tautomeric set in solution. In solid form,usually one tautomer predominates. In solutions where tautomerization ispossible, a chemical equilibrium of the tautomers will be reached. Theexact ratio of the tautomers depends on several factors, includingtemperature, solvent and pH. The concept of tautomers that areinterconvertable by tautomerizations is called tautomerism.

Of the various types of tautomerism that are possible, two are commonlyobserved. In keto-enol tautomerism a simultaneous shift of electrons anda hydrogen atom occurs. Ring-chain tautomerism arises as a result of thealdehyde group (—CHO) in a sugar chain molecule reacting with one of thehydroxy groups (—OH) in the same molecule to give it a cyclic(ring-shaped) form as exhibited by glucose.

Common tautomeric pairs are: ketone-enol, amide-nitrile, lactam-lactim,amide-imidic acid tautomerism in heterocyclic rings (e.g., innucleobases such as guanine, thymine and cytosine), amine-enamine andenamine-imine.

It is to be understood that the compounds of the present application maybe depicted as different tautomers. It should also be understood thatwhen compounds have tautomeric forms, all tautomeric forms are intendedto be included in the scope of the present application, and the namingof the compounds does not exclude any tautomer form. Tautomeric forms ofthe compounds of each of the formulae described herein are included inthe present application.

The application also comprehends isotopically-labeled compounds, whichare identical to those recited in the each of the formulae describedherein, but for the fact that one or more atoms are replaced by an atomhaving an atomic mass or mass number different from the atomic mass ormass number most commonly found in nature. Examples of isotopes that canbe incorporated into compounds of the application include isotopes ofhydrogen, carbon, nitrogen, fluorine, such as ³H, ¹¹C, ¹⁴C, ²H and ¹⁸F.

Compounds of each of the formulae described herein or pharmaceuticallyacceptable salts thereof, that contain the aforementioned isotopesand/or other isotopes of other atoms are within the scope of the presentapplication. Isotopically-labeled compounds of the present application,for example those into which radioactive isotopes such as ³H, ¹⁴C areincorporated, are useful in drug and/or substrate tissue distributionassays. Tritiated, i.e., ³H, and carbon-14, i.e., ¹⁴C, isotopes areuseful for their ease of preparation and detectability. ¹¹C and ¹⁸Fisotopes are useful in PET (positron emission tomography). PET is usefulin brain imaging. Further, substitution with heavier isotopes such asdeuterium, i.e., ²H, can afford certain therapeutic advantages resultingfrom greater metabolic stability, for example increased in vivohalf-life or reduced dosage requirements and, hence, may be preferred insome circumstances, isotopically labeled compounds of the formulaedescribed herein or pharmaceutically acceptable salts, tautomers,prodrugs, solvates, metabolites, polymorphs, analogs or derivativesthereof, can generally be prepared by carrying out the proceduresdisclosed in the Schemes and/or in the Examples described herein, bysubstituting a readily available isotopically labeled reagent for anon-isotopically labeled reagent. In one embodiment, the compounds ofthe formulae described herein or pharmaceutically acceptable salts,tautomers, prodrugs, solvates, metabolites, polymorphs, analogs orderivatives thereof, are not isotopically labelled.

2. Synthesis of Compounds of the Present Application

The present application provides methods for the synthesis of thecompounds of each of the formulae described herein or pharmaceuticallyacceptable salts thereof. The present application also provides detailedmethods for the synthesis of various disclosed compounds of each of theformulae described herein or pharmaceutically acceptable salts thereofaccording to the following schemes and/or as shown in the examples.

Throughout the description, where compositions are described as having,including, or comprising specific components, it is contemplated thatcompositions also consist essentially of, or consist of, the recitedcomponents. Similarly, where methods or processes are described ashaving, including, or comprising specific process steps, the processesalso consist essentially of, or consist of, the recited processingsteps. Further, it should be understood that the order of steps or orderfor performing certain actions is immaterial so long as the applicationremains operable. Moreover, two or more steps or actions can beconducted simultaneously.

The synthetic processes of the application can tolerate a wide varietyof functional groups in the compounds prepared, therefore varioussubstituted starting materials can be used. The processes generallyprovide the desired final compound at or near the end of the overallprocess, although it may be desirable in certain instances to furtherconvert the compound to a pharmaceutically acceptable salt thereof.

Compounds of the present application or pharmaceutically acceptablesalts thereof can be prepared in a variety of ways using commerciallyavailable starting materials, compounds known in the literature, or fromreadily prepared intermediates, by employing standard synthetic methodsand procedures either known to those skilled in the art, or which willbe apparent to the skilled artisan in light of the teachings herein.Standard synthetic methods and procedures for the preparation of organicmolecules and functional group transformations and manipulations can beobtained from the relevant scientific literature or from standardtextbooks in the field. Although not limited to any one or severalsources, classic texts such as Smith, M. B., March, J., March's AdvancedOrganic Chemistry: Reactions, Mechanisms, and Structure, 5^(th) edition,John Wiley & Sons: New York, 2001; and Greene, T. W., Wuts, P. G. M.,Protective Groups in Organic Synthesis, 3rd edition, John Wiley & Sons:New York, 1999, incorporated by reference herein, are useful andrecognized reference textbooks of organic synthesis known to those inthe art. The following descriptions of synthetic methods are designed toillustrate, but not to limit, general procedures for the preparation ofcompounds of the present application or pharmaceutically acceptablesalts, tautomers, prodrugs, solvates, metabolites, polymorphs, analogsor derivatives thereof.

Compounds of the present application can be conveniently prepared by avariety of methods familiar to those skilled in the art. The compoundseach of the formulae described herein may be prepared according to thefollowing procedures from commercially available starting materials orstarting materials which can be prepared using literature procedures.These procedures show the preparation of representative compounds ofthis application.

All the abbreviations used in this application are found in “ProtectiveGroups in Organic Synthesis” by John Wiley & Sons, Inc, or the MERCKINDEX by MERCK & Co., Inc, or other chemistry books or chemicalscatalogs by chemicals vendor such as Aldrich, or according to usage knowin the art.

The physicochemical properties and biological activities of thecompounds of the present application can be assessed using methods andmaterials known in the art. For example, the stability of the compoundsmay be evaluated by incubating the compounds of the present applicationwith serum for various periods of time and then measuring the remainingamount of the compounds through common analytic methods, such as massspectrometry (e.g., LC-MS). In another example, the cell growthinhibitory activity of the compounds of the present application may beassessed by treating cancer cells with various concentrations of thecompounds for different time periods, and then measuring the number ofviable cells by common techniques, such as luminescence assays. Inaddition, the ability of the compounds of the present application toregulate the Hh signaling pathway may be determined by treating cellswith the compounds of the present application and then measuring theexpression of the targeted genes (e.g., Gill or Ptch) or a reporter gene(e.g., luciferase).

3. Biological Assays

Stability Measurements

SMO antagonists are incubated at selected concentration(s) in serum orserum-free cell culture media at 37° C. for varying lengths of time.Reactions are terminated by cold acetonitrile. Samples are centrifugedand the supernatant is removed and filtered, before measurement byLC-MS. The percent remaining of each compound is calculated by theintegrated area of the peak at each time point divided by the peak atthe t=0 time point. Data is fit to a one-phase decay curve usingGraphPad Prism 6 software.

Cell Viability

Sample cells (e.g., SmoWT-MB cells, a mouse medulloblastoma cell linewith wild-type Smo and Ptch1 loss of function) are distributed intoculture plates and then pinned with SMO antagonists in quadruplicateover a ten-point dose range. Cell viability, relative to control treatedcells, is measured after various time points after treatment (e.g., 24,48, 72, or 96 hours) by ATPlite. IC₅₀ is determined by fittingdose-response curves in GraphPad Prism 6 software.

Gene Expression Analysis

Sample cells (e.g., SmoWT-MB cells) are plated in culture plates, grownfor 24 hours, and treated with SMO antagonists for 24 hours. Aftertreatment, RNA is extracted from cells and cDNA is prepared from theRNA. The fold-change in expression for the gene(s) of interest (e.g.,Gli1 and Ptch1), relative to control is determined by qRT-PCR using theΔΔC_(t) method.

Hh Pathway Cell Reporter Assays

Sample cells (e.g., Shh-LightII cells, NIH-3T3 cells stably expressingGli-dependent firefly luciferase and constitutively active Renillaluciferase) are distributed into culture plates and grown for 48 hours.Cells are changed to serum-free media and Hh pathway activity isstimulated by treatment with Smoothened agonist (SAG). Cells are treatedwith SMO antagonist for 24 hours (or for 24 hours with an additionaldose after 20 hours) and luciferase activity (normalized to Renillaluciferase and relative to DMSO treated cells) is measured using theDual Luciferase Reporter Assay kit (Promega) as a surrogate for Hhpathway activation.

4. Methods of Treatment

The present application provides methods for regulating the Hh signalingpathway, by using a compound of the present application, or apharmaceutically acceptable salt thereof. In one embodiment, a compoundof the present application regulates the Hh signaling pathway byinhibiting or decreasing the activity of SMO. Accordingly, disordersmediated by the Hh signaling pathway (e.g., activity of SMO) can betreated by the compound of the present application, or apharmaceutically acceptable salt thereof.

The present application provides methods for the treatment of a disordermediated by the Hh signaling pathway (e.g., the disorders describedherein, such as medulloblastoma (MB) and basal cell carcinoma (BCC)) ina subject in need thereof by administering to the subject, atherapeutically effective amount of a compound of the presentapplication, or a pharmaceutically acceptable salt thereof. The disordercan be a cell proliferative disorder, and the cell proliferativedisorder can be cancer or a precancerous condition. The presentapplication further provides the use of a compound of the presentapplication, or a pharmaceutically acceptable salt thereof, for thetreatment of a disorder mediated by the Hh signaling pathway. Thepresent application further provides the use of a compound of thepresent application, or a pharmaceutically acceptable salt thereof, forthe preparation of a medicament useful for the treatment of a disordermediated by the Hh signaling pathway.

The present application also provides methods of protecting against adisorder mediated by the Hh signaling pathway (e.g., the disordersdescribed herein, such as medulloblastoma (MB) and basal cell carcinoma(BCC)) in a subject in need thereof by administering to the subject atherapeutically effective amount of compound of the present application,or a pharmaceutically acceptable salt thereof. The disorder can be acell proliferative disorder, and the cell proliferative disorder can becancer or a precancerous condition. The present application alsoprovides the use of a compound of the present application, or apharmaceutically acceptable salt thereof, for the prevention of adisorder mediated by the Hh signaling pathway. The present applicationalso provides the use of a compound of the present application, or apharmaceutically acceptable salt thereof, for the preparation of amedicament useful for the prevention of a disorder mediated by the Hhsignaling pathway.

In one aspect, the compounds or compositions of the present applicationare administered topically to a subject in need thereof.

As used herein, a “subject in need thereof” is a subject having adisorder mediated by the Hh signaling pathway, or a subject having anincreased risk of developing a disorder mediated by the Hh signalingpathway relative to the population at large. A subject in need thereofcan have a precancerous condition mediated by the Hh signaling pathway.For example, a subject in need thereof has cancer mediated by the Hhsignaling pathway. A “subject” includes a mammal. The mammal can bee.g., any mammal, e.g., a human, primate, bird, mouse, rat, fowl, dog,cat, cow, horse, goat, camel, sheep or a pig. Preferably, the mammal isa human.

As used herein, the term “cell proliferative disorder” refers toconditions in which unregulated or abnormal growth, or both, of cellscan lead to the development of an unwanted condition or disease, whichmay or may not be cancerous. Exemplary cell proliferative disorders ofthe application encompass a variety of conditions wherein cell divisionis deregulated. Exemplary cell proliferative disorder include, but arenot limited to, neoplasms, benign tumors, malignant tumors,pre-cancerous conditions, in situ tumors, encapsulated tumors,metastatic tumors, liquid tumors, solid tumors, immunological tumors,hematological tumors, cancers, carcinomas, leukemias, lymphomas,sarcomas, and rapidly dividing cells.

The term “rapidly dividing cell” as used herein is defined as any cellthat divides at a rate that exceeds or is greater than what is expectedor observed among neighboring or juxtaposed cells within the sametissue. A cell proliferative disorder includes a precancer or aprecancerous condition. A cell proliferative disorder includes cancer.

The term “cancer” includes solid tumors, as well as, hematologic tumorsand/or malignancies. A “precancer cell” or “precancerous cell” is a cellmanifesting a cell proliferative disorder that is a precancer or aprecancerous condition. A “cancer cell” or “cancerous cell” is a cellmanifesting a cell proliferative disorder that is a cancer. Anyreproducible means of measurement may be used to identify cancer cellsor precancerous cells. Cancer cells or precancerous cells can beidentified by histological typing or grading of a tissue sample (e.g., abiopsy sample). Cancer cells or precancerous cells can be identifiedthrough the use of appropriate molecular markers.

Examplary disorders mediated by the Hh signaling pathway include, butare not lited to, cancer (e.g., pancreatic cancer, colon cancer, lungcancer, esophageal cancer, gastroesophageal cancer, gastric cancer,breast cancer, ovarian cancer, prostate cancer, skin cancer, leukemias,multiple myeloma, chronic myeloid leukemia, medulloblastoma (MB), basalcell carcinoma (BCC), meningioma, and ameloblastoma), macrocephaly, riband vertebrae anomalies, intracranial calcification, skeletalabnormalities (e.g., bifid ribs, kyphoscoliosis, early calcification offalx cerebri, sprengel deformity, pectus deformity, polydactyly,syndactyly, or hypertelorism), distinct faces (e.g., frontal andtemporoparietal bossing, hypertelorism, mandibular prognathism, cleftlip or palate), eye anomaly (e.g., cataract, coloboma (of the iris,choroid and optic nerve, strabismus, and nystagmus), orbital cyst,microphthalmia, nystagmus), odontogenic keratocysts, hypogonadism,kidney anomalies (e.g., horseshoe kidney, L-shaped kidney, unilateralrenal agenesis, renal cyst, and duplication of renal pelvis andureters), Gorlin syndrome, keratocystic odontogenic tumor, ovarian, andcardio fibroma. In one embodiment, disorders mediated by the Hhsignaling pathway are selected from medulloblastoma (MB) and basal cellcarcinoma (BCC).

A “cell proliferative disorder of the skin” is a cell proliferativedisorder involving cells of the skin. Cell proliferative disorders ofthe skin can include all forms of cell proliferative disorders affectingskin cells. Cell proliferative disorders of the skin can include aprecancer or precancerous condition of the skin, benign growths orlesions of the skin, melanoma, malignant melanoma and other non-melanomamalignant growths or lesions of the skin, and metastatic lesions intissue and organs in the body other than the skin. Cell proliferativedisorders of the skin can include hyperplasia, metaplasia, and dysplasiaof the skin.

As used herein, a “normal cell” is a cell that cannot be classified aspart of a “cell proliferative disorder”. A normal cell lacks unregulatedor abnormal growth, or both, that can lead to the development of anunwanted condition or disease. Preferably, a normal cell possessesnormally functioning cell cycle checkpoint control mechanisms.

As used herein, “treating” or “treat” describes the management and careof a patient for the purpose of combating a disease, condition, ordisorder and includes the administration of a compound of the presentapplication, or a pharmaceutically acceptable salt thereof, to alleviatethe symptoms or complications of a disease, condition or disorder, or toeliminate the disease, condition or disorder.

As used herein, “preventing” or “prevent” describes reducing oreliminating the onset of the symptoms or complications of the disease,condition or disorder.

As used herein, the term “alleviating” or “alleviate” is meant todescribe a process by which the severity of a sign or symptom of adisorder is decreased. Importantly, a sign or symptom can be alleviatedwithout being eliminated. In a preferred embodiment, the administrationof pharmaceutical compositions of the application leads to theelimination of a sign or symptom, however, elimination is not required.Effective dosages are expected to decrease the severity of a sign orsymptom. For instance, a sign or symptom of a disorder such as cancer,which can occur in multiple locations, is alleviated if the severity ofthe cancer is decreased within at least one of multiple locations.

As used herein the term “symptom” is defined as an indication ofdisease, illness, injury, or that something is not right in the body.Symptoms are felt or noticed by the individual experiencing the symptom,but may not easily be noticed by others. Others are defined asnon-health-care professionals.

As used herein the term “sign” is also defined as an indication thatsomething is not right in the body, but signs are defined as things thatcan be seen by a doctor, nurse, or other health care professional.

A compound of the present application, or a pharmaceutically acceptablesalt thereof, can modulate the activity of a molecular target (e.g.,SMO). Modulating refers to stimulating or inhibiting an activity of amolecular target. Preferably, a compound of the present application, ora pharmaceutically acceptable salt thereof, modulates the activity of amolecular target if it stimulates or inhibits the activity of themolecular target by at least 2-fold relative to the activity of themolecular target under the same conditions but lacking only the presenceof the compound. More preferably, a compound of the present application,or a pharmaceutically acceptable salt thereof, modulates the activity ofa molecular target if it stimulates or inhibits the activity of themolecular target by at least 5-fold, at least 10-fold, at least 20-fold,at least 50-fold, at least 100-fold relative to the activity of themolecular target under the same conditions but lacking only the presenceof the compound. The activity of a molecular target may be measured byany reproducible means. The activity of a molecular target may bemeasured in vitro or in vivo. For example, the activity of a moleculartarget may be measured in vitro by an enzymatic activity assay or a DNAbinding assay, or the activity of a molecular target may be measured invivo by assaying for expression of a reporter gene.

One skilled in the art may refer to general reference texts for detaileddescriptions of known techniques discussed herein or equivalenttechniques. These texts include Ausubel et al., Current Protocols inMolecular Biology, John Wiley and Sons, Inc. (2005); Sambrook et al.,Molecular Cloning, A Laboratory Manual (3^(rd) edition), Cold SpringHarbor Press, Cold Spring Harbor, N.Y. (2000); Coligan et al., CurrentProtocols in Immunology, John Wiley & Sons, N.Y.; Enna et al., CurrentProtocols in Pharmacology, John Wiley & Sons, N.Y.; Fingl et al., ThePharmacological Basis of Therapeutics (1975), Remington's PharmaceuticalSciences, Mack Publishing Co., Easton, Pa., 18^(th) edition (1990).These texts can, of course, also be referred to in making or using anaspect of the application

5. Pharmaceutical Compositions

The present application also provides pharmaceutical compositionscomprising a compound of any of the formulae described herein incombination with at least one pharmaceutically acceptable excipient orcarrier.

A “pharmaceutical composition” is a formulation containing the compoundsof the present application in a form suitable for administration to asubject. In one embodiment, the pharmaceutical composition is in bulk orin unit dosage form. The unit dosage form is any of a variety of forms,including, for example, a capsule, an IV bag, a tablet, a single pump onan aerosol inhaler or a vial. The quantity of active ingredient (e.g., aformulation of the disclosed compound or a pharmaceutically acceptablesalt thereof) in a unit dose of composition is an effective amount andis varied according to the particular treatment involved. One skilled inthe art will appreciate that it is sometimes necessary to make routinevariations to the dosage depending on the age and condition of thepatient. The dosage will also depend on the route of administration. Avariety of routes are contemplated, including oral, topical, parenteral,transdermal, subcutaneous, intravenous, intramuscular, intraperitoneal,inhalational, buccal, sublingual, intrapleural, intrathecal, intranasal,and the like. Dosage forms for the topical or transdermal administrationof a compound of this application include powders, sprays, ointments,pastes, creams, lotions, gels, solutions, patches and inhalants. In oneembodiment, the active compound is mixed under sterile conditions with apharmaceutically acceptable carrier, and with any preservatives, buffersor propellants that are required.

As used herein, the phrase “pharmaceutically acceptable” refers to thosecompounds, materials, compositions, carriers, and/or dosage forms whichare, within the scope of sound medical judgment, suitable for use incontact with the tissues of human beings and animals without excessivetoxicity, irritation, allergic response, or other problem orcomplication, commensurate with a reasonable benefit/risk ratio.

“Pharmaceutically acceptable excipient” means an excipient that isuseful in preparing a pharmaceutical composition that is generally safe,non-toxic and neither biologically nor otherwise undesirable, andincludes excipient that is acceptable for veterinary use as well ashuman pharmaceutical use. A “pharmaceutically acceptable excipient” asused in the specification and claims includes both one and more than onesuch excipient.

A pharmaceutical composition of the application is formulated to becompatible with its intended route of administration. Examples of routesof administration include parenteral, e.g., intravenous, intradermal,subcutaneous, oral (e.g., inhalation), transdermal (topical), andtransmucosal administration. Solutions or suspensions used forparenteral, intradermal, or subcutaneous application can include thefollowing components: a sterile diluent such as water for injection,saline solution, fixed oils, polyethylene glycols, glycerine, propyleneglycol or other synthetic solvents; antibacterial agents such as benzylalcohol or methyl parabens; antioxidants such as ascorbic acid or sodiumbisulfate; chelating agents such as ethylenediaminetetraacetic acid;buffers such as acetates, citrates or phosphates, and agents for theadjustment of tonicity such as sodium chloride or dextrose. The pH canbe adjusted with acids or bases, such as hydrochloric acid or sodiumhydroxide. The parenteral preparation can be enclosed in ampoules,disposable syringes or multiple dose vials made of glass or plastic.

A compound or pharmaceutical composition of the application can beadministered to a subject in many of the well-known methods currentlyused for chemotherapeutic treatment. The dose chosen should besufficient to constitute effective treatment but not as high as to causeunacceptable side effects. The state of the disease condition (e.g.,cancer, precancer, and the like) and the health of the patient shouldpreferably be closely monitored during and for a reasonable period aftertreatment.

The term “therapeutically effective amount”, as used herein, refers toan amount of a pharmaceutical agent to treat, ameliorate, or prevent anidentified disease or condition, or to exhibit a detectable therapeuticor inhibitory effect. The effect can be detected by any assay methodknown in the art. The precise effective amount for a subject will dependupon the subject's body weight, size, and health; the nature and extentof the condition; and the therapeutic or combination of therapeuticsselected for administration. Therapeutically effective amounts for agiven situation can be determined by routine experimentation that iswithin the skill and judgment of the clinician. In a preferred aspect,the disease or condition to be treated is cancer. In another aspect, thedisease or condition to be treated is a cell proliferative disorder.

For any compound, the therapeutically effective amount can be estimatedinitially either in cell culture assays, e.g., of neoplastic cells, orin animal models, usually rats, mice, rabbits, dogs, or pigs. The animalmodel may also be used to determine the appropriate concentration rangeand route of administration. Such information can then be used todetermine useful doses and routes for administration in humans.Therapeutic/prophylactic efficacy and toxicity may be determined bystandard pharmaceutical procedures in cell cultures or experimentalanimals, e.g., ED₅₀ (the dose therapeutically effective in 50% of thepopulation) and LD₅₀ (the dose lethal to 50% of the population). Thedose ratio between toxic and therapeutic effects is the therapeuticindex, and it can be expressed as the ratio, LD₅₀/ED₅₀. Pharmaceuticalcompositions that exhibit large therapeutic indices are preferred. Thedosage may vary within this range depending upon the dosage formemployed, sensitivity of the patient, and the route of administration.

Dosage and administration are adjusted to provide sufficient levels ofthe active agent(s) or to maintain the desired effect. Factors which maybe taken into account include the severity of the disease state, generalhealth of the subject, age, weight, and gender of the subject, diet,time and frequency of administration, drug combination(s), reactionsensitivities, and tolerance/response to therapy. Long-actingpharmaceutical compositions may be administered every 3 to 4 days, everyweek, or once every two weeks depending on half-life and clearance rateof the particular formulation.

The pharmaceutical compositions containing active compounds of thepresent application may be manufactured in a manner that is generallyknown, e.g., by means of conventional mixing, dissolving, granulating,dragee-making, levigating, emulsifying, encapsulating, entrapping, orlyophilizing processes. Pharmaceutical compositions may be formulated ina conventional manner using one or more pharmaceutically acceptablecarriers comprising excipients and/or auxiliaries that facilitateprocessing of the active compounds into preparations that can be usedpharmaceutically. Of course, the appropriate formulation is dependentupon the route of administration chosen.

Pharmaceutical compositions suitable for injectable use include sterileaqueous solutions (where water soluble) or dispersions and sterilepowders for the extemporaneous preparation of sterile injectablesolutions or dispersion. For intravenous administration, suitablecarriers include physiological saline, bacteriostatic water, CremophorEL™ (BASF, Parsippany, N.J.) or phosphate buffered saline (PBS). In allcases, the composition must be sterile and should be fluid to the extentthat easy syringeability exists. It must be stable under the conditionsof manufacture and storage and must be preserved against thecontaminating action of microorganisms such as bacteria and fungi. Thecarrier can be a solvent or dispersion medium containing, for example,water, ethanol, polyol (for example, glycerol, propylene glycol, andliquid polyethylene glycol, and the like), and suitable mixturesthereof. The proper fluidity can be maintained, for example, by the useof a coating such as lecithin, by the maintenance of the requiredparticle size in the case of dispersion and by the use of surfactants.Prevention of the action of microorganisms can be achieved by variousantibacterial and antifungal agents, for example, parabens,chlorobutanol, phenol, ascorbic acid, thimerosal, and the like. In manycases, it will be preferable to include isotonic agents, for example,sugars, polyalcohols such as manitol, sorbitol, sodium chloride in thecomposition. Prolonged absorption of the injectable compositions can bebrought about by including in the composition an agent which delaysabsorption, for example, aluminum monostearate and gelatin.

Sterile injectable solutions can be prepared by incorporating the activecompound in the required amount in an appropriate solvent with one or acombination of ingredients enumerated above, as required, followed byfiltered sterilization. Generally, dispersions are prepared byincorporating the active compound into a sterile vehicle that contains abasic dispersion medium and the required other ingredients from thoseenumerated above. In the case of sterile powders for the preparation ofsterile injectable solutions, methods of preparation are vacuum dryingand freeze-drying that yields a powder of the active ingredient plus anyadditional desired ingredient from a previously sterile-filteredsolution thereof.

Oral compositions generally include an inert diluent or an ediblepharmaceutically acceptable carrier. They can be enclosed in gelatincapsules or compressed into tablets. For the purpose of oral therapeuticadministration, the active compound can be incorporated with excipientsand used in the form of tablets, troches, or capsules. Oral compositionscan also be prepared using a fluid carrier for use as a mouthwash,wherein the compound in the fluid carrier is applied orally and swishedand expectorated or swallowed. Pharmaceutically compatible bindingagents, and/or adjuvant materials can be included as part of thecomposition. The tablets, pills, capsules, troches and the like cancontain any of the following ingredients, or compounds of a similarnature: a binder such as microcrystalline cellulose, gum tragacanth orgelatin; an excipient such as starch or lactose; a disintegrating agentsuch as alginic acid, Primogel, or corn starch; a lubricant such asmagnesium stearate or Sterotes; a glidant such as colloidal silicondioxide; a sweetening agent such as sucrose or saccharin; or a flavoringagent such as peppermint, methyl salicylate, or orange flavoring.

For administration by inhalation, the compounds are delivered in theform of an aerosol spray from pressured container or dispenser, whichcontains a suitable propellant, e.g., a gas such as carbon dioxide, or anebulizer.

Systemic administration can also be by transmucosal or transdermalmeans. For transmucosal or transdermal administration, penetrantsappropriate to the barrier to be permeated are used in the formulation.Such penetrants are generally known in the art, and include, forexample, for transmucosal administration, detergents, bile salts, andfusidic acid derivatives. Transmucosal administration can beaccomplished through the use of nasal sprays or suppositories. Fortransdermal administration, the active compounds are formulated intoointments, salves, gels, or creams as generally known in the art.

The pharmaceutical composition of the present application may beadministered topically. The topical formulation of the presentapplication may be in the form of a solution comprising water and atleast one pharmaceutically acceptable excipient. Suitable excipientsinclude those selected from the group consisting of a solubilityenhancing agent, chelating agent, preservative, tonicity agent,viscosity/suspending agent, buffer, and pH modifying agent, and amixture thereof.

Any suitable solubility enhancing agent can be used. Examples of asolubility enhancing agent include cyclodextrin, such as those selectedfrom the group consisting of hydroxypropyl-O-cyclodextrin,methyl-β-cyclodextrin, randomly methylated-β-cyclodextrin,ethylated-O-cyclodextrin, triacetyl-O-cyclodextrin,peracetylated-O-cyclodextrin, carboxymethyl-β-cyclodextrin,hydroxyethyl-β-cyclodextrin,2-hydroxy-3-(trimethylammonio)propyl-β-cyclodextrin,glucosyl-β-cyclodextrin, sulphated β-cyclodextrin (S-β-CD),maltosyl-β-cyclodextrin, β-cyclodextrin sulfobutyl ether,branched-β-cyclodextrin, hydroxypropyl-γ-cyclodextrin, randomlymethylated-γ-cyclodextrin, and trimethyl-γ-cyclodextrin, and mixturesthereof.

Any suitable chelating agent can be used. Examples of a suitableophthalmically acceptable chelating agent include those selected fromthe group consisting of ethylenediaminetetraacetic acid and metal saltsthereof, disodium edetate, trisodium edetate, and tetrasodium edetate,and mixtures thereof.

The aqueous vehicle may also include a preservative. Preservativesinclude those selected from the group consisting of quaternary ammoniumsalts such as benzalkonium halides (preferably benzalkonium chloride),chlorhexidine gluconate, benzethonium chloride, cetyl pyridiniumchloride, benzyl bromide, phenylmercury nitrate, phenylmercury acetate,phenylmercury neodecanoate, merthiolate, methylparaben, propylparaben,sorbic acid, potassium sorbate, sodium benzoate, sodium propionate,ethyl p-hydroxybenzoate, propylaminopropyl biguanide, andbutyl-p-hydroxybenzoate, sorbic acid, and mixtures thereof.

The aqueous vehicle may also include a tonicity agent to adjust thetonicity (osmotic pressure). The tonicity agent can be selected from thegroup consisting of a glycol (such as propylene glycol, diethyleneglycol, triethylene glycol), glycerol, dextrose, glycerin, mannitol,potassium chloride, and sodium chloride, and a mixture thereof.

The aqueous vehicle may also contain a viscosity/suspending agent.Suitable viscosity/suspending agents include those selected from thegroup consisting of cellulose derivatives, such as methyl cellulose,ethyl cellulose, hydroxyethylcellulose, polyethylene glycols (such aspolyethylene glycol 300, polyethylene glycol 400), carboxymethylcellulose, hydroxypropylmethyl cellulose, and cross-linked acrylic acidpolymers (carbomers), such as polymers of acrylic acid cross-linked withpolyalkenyl ethers or divinyl glycol (Carbopols—such as Carbopol 934,Carbopol 934P, Carbopol 971, Carbopol 974 and Carbopol 974P), and amixture thereof.

The topical formulation may contain a pH modifying agent. The pHmodifying agent is typically a mineral acid or metal hydroxide base,selected from the group of potassium hydroxide, sodium hydroxide, andhydrochloric acid, and mixtures thereof, and preferably sodium hydroxideand/or hydrochloric acid. These acidic and/or basic pH modifying agentsare added to adjust the formulation to the target ophthalmicallyacceptable pH range. Hence it may not be necessary to use both acid andbase—depending on the formulation, the addition of one of the acid orbase may be sufficient to bring the mixture to the desired pH range.

The topical formulation may also contain a buffering agent to stabilizethe pH. When used, the buffer is selected from the group consisting of aphosphate buffer (such as sodium dihydrogen phosphate and disodiumhydrogen phosphate), a borate buffer (such as boric acid, or saltsthereof including disodium tetraborate), a citrate buffer (such ascitric acid, or salts thereof including sodium citrate), andε-aminocaproic acid, and mixtures thereof.

The topical formulation may further comprise a wetting agent. Thewetting agent may be a non-ionic wetting agent. Suitable classes ofwetting agents include those selected from the group consisting ofpolyoxypropylene-polyoxyethylene block copolymers (poloxamers),polyethoxylated ethers of castor oils, polyoxyethylenated sorbitanesters (polysorbates), polymers of oxyethylated octyl phenol(Tyloxapol), polyoxyl 40 stearate, fatty acid glycol esters, fatty acidglyceryl esters, sucrose fatty esters, and polyoxyethylene fatty esters,and mixtures thereof.

The topical formulation of the present application may also be in theform of a gel or a semi-gel, or both; a jelly; a suspension; anemulsion; an oil; an ointment; a cream; or a spray.

The topical gel, semi-gel, jelly, suspension, emulsion, oil, ointment,cream, or spray may contain various additives incorporated ordinarily,such as buffering agents (e.g., phosphate buffers, borate buffers,citrate buffers, tartrate buffers, acetate buffers, amino acids, sodiumacetate, sodium citrate and the like), tonicity agents (e.g.,saccharides such as sorbitol, glucose and mannitol, polyhydric alcoholssuch as glycerin, concentrated glycerin, PEG and propylene glycol, saltssuch as sodium chloride), preservatives or antiseptics (e.g.,benzalkonium chloride, benzalkonium chloride, P-oxybenzoates such asmethyl p-oxybenzoate or ethyl p-oxybenzoate, benzyl alcohol, phenethylalcohol, sorbic acid or its salt, thimerosal, chlorobutanol and thelike), solubilizing enhancing agents (e.g., cyclodextrins and theirderivative, water-soluble polymers such as polyvinyl pyrrolidone,surfactants such as tyloxapol, polysorbates), pH modifiers (e.g.,hydrochloric acid, acetic acid, phosphoric acid, sodium hydroxide,potassium hydroxide, ammonium hydroxide and the like), thickening agents(e.g., HEC, hydroxypropyl cellulose, methyl cellulose, HPMC,carboxymethyl cellulose and their salts), chelating agents (e.g., sodiumedetate, sodium citrate, condensed sodium phosphate) and the like.

Furthermore the compounds of the application may be formulated fortopical administration by incorporation into topical formulationsincluding but not limited to: microemulsions, liposomes, niosomes, gels,hydrogel, nanoparticles, and nanosuspension.

The compounds of the application may also be coupled with solublepolymers as targetable drug carriers. Such polymers can includepolyvinylpyrrolidone, pyran copolymer,polyhydroxypropylmethacrylamide-phenol,polyhydroxyethylaspartamide-phenol, and polyethyleneoxide-polylysinesubstituted with palmitoyl residues. Furthermore, the compounds of theapplication may be coupled to a class of biodegradable polymers usefulin achieving controlled release of a drug, for example, polylactic acid,polyglycolic acid, copolymers of polylactic and polyglycolic acid,polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters,polyacetals, polydihydropyrans, polycyanoacrylates and crosslinked oramphipathic block copolymers of hydrogels.

The active compounds can be prepared with pharmaceutically acceptablecarriers that will protect the compound against rapid elimination fromthe body, such as a controlled release formulation, including implantsand microencapsulated delivery systems. Biodegradable, biocompatiblepolymers can be used, such as ethylene vinyl acetate, polyanhydrides,polyglycolic acid, collagen, polyorthoesters, and polylactic acid.Methods for preparation of such formulations will be apparent to thoseskilled in the art.

The pharmaceutical compositions can be included in a container, pack, ordispenser together with instructions for administration.

The compounds of the present application are capable of further formingsalts. All of these forms are also contemplated within the scope of theclaimed application.

As used herein, “pharmaceutically acceptable salts” refer to derivativesof the compounds of the present application wherein the parent compoundis modified by making acid or base salts thereof. Examples ofpharmaceutically acceptable salts include, but are not limited to,mineral or organic acid salts of basic residues such as amines, alkalior organic salts of acidic residues such as carboxylic acids, and thelike. The pharmaceutically acceptable salts include the conventionalnon-toxic salts or the quaternary ammonium salts of the parent compoundformed, for example, from non-toxic inorganic or organic acids. Forexample, such conventional non-toxic salts include, but are not limitedto, those derived from inorganic and organic acids selected from2-acetoxybenzoic, 2-hydroxyethane sulfonic, acetic, ascorbic, benzenesulfonic, benzoic, bicarbonic, carbonic, citric, edetic, ethanedisulfonic, 1,2-ethane sulfonic, fumaric, glucoheptonic, gluconic,glutamic, glycolic, glycollyarsanilic, hexylresorcinic, hydrabamic,hydrobromic, hydrochloric, hydroiodic, hydroxymaleic, hydroxynaphthoic,isethionic, lactic, lactobionic, lauryl sulfonic, maleic, malic,mandelic, methane sulfonic, napsylic, nitric, oxalic, pamoic,pantothenic, phenylacetic, phosphoric, polygalacturonic, propionic,salicyclic, stearic, subacetic, succinic, sulfamic, sulfanilic,sulfuric, tannic, tartaric, toluene sulfonic, and the commonly occurringamine acids, e.g., glycine, alanine, phenylalanine, arginine, etc.

Other examples of pharmaceutically acceptable salts include hexanoicacid, cyclopentane propionic acid, pyruvic acid, malonic acid,3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, 4-chlorobenzenesulfonicacid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid,camphorsulfonic acid, 4-methylbicyclo-[2.2.2]-oct-2-ene-1-carboxylicacid, 3-phenylpropionic acid, trimethylacetic acid, tertiary butylaceticacid, muconic acid, and the like. The present application alsoencompasses salts formed when an acidic proton present in the parentcompound either is replaced by a metal ion, e.g., an alkali metal ion,an alkaline earth ion, or an aluminum ion; or coordinates with anorganic base such as ethanolamine, diethanolamine, triethanolamine,tromethamine, N-methylglucamine, and the like.

Techniques for formulation and administration of the disclosed compoundsof the application can be found in Remington: the Science and Practiceof Pharmacy, 19th edition, Mack Publishing Co., Easton, Pa. (1995). Inan embodiment, the compounds described herein, and the pharmaceuticallyacceptable salts, tautomers, prodrugs, solvates, metabolites,polymorphs, analogs or derivatives thereof, are used in pharmaceuticalpreparations in combination with a pharmaceutically acceptable carrieror diluent. Suitable pharmaceutically acceptable carriers include inertsolid fillers or diluents and sterile aqueous or organic solutions. Thecompounds or pharmaceutically acceptable salts, prodrugs, solvates,metabolites, polymorphs, analogs or derivatives thereof will be presentin such pharmaceutical compositions in amounts sufficient to provide thedesired dosage amount in the range described herein.

All percentages and ratios used herein, unless otherwise indicated, areby weight. Other features and advantages of the present application areapparent from the different examples. The provided examples illustratedifferent components and methodology useful in practicing the presentapplication. The examples do not limit the claimed application. Based onthe present disclosure the skilled artisan can identify and employ othercomponents and methodology useful for practicing the presentapplication.

EXAMPLES Example 1: Synthesis of Vismoister

Synthesis of 3:

A mixture of 1 (500 mg, 2.9 mmol), 2 (300 g, 2.0 mmol), K₃PO₄ (1.27 mg,6 mmol) and Pd(PPh₃)₄ (230 mg, 0.2 mmol) in 20 mL of DMF and 5 mL of H₂Owas stirred under N2 protection at 80° C. for 17 hours. The reactionmixture was cooled to room temperature, diluted with 100 mL of water andextracted with ethyl acetate (80 mL×3). The combined organic phases werewashed brine (100 mL), dried over anhydrous Na₂SO₄ and filtered. Thefiltrated was concentrated in vacuo. The residue was further purified byreverse flash chromatography (NH₄HCO₃/H₂O:CH₃CN=70:30) to give 3 asyellow solid (220 mg, yield: 53.6%). LC-MS m/z: 206.1 [M+H]⁺. LC-MSPurity (214 nm): >82%; t_(R)=1.447 min.

Synthesis of Vismoister:

To a mixture of 4 (140.4 mg, 0.6 mmol) in 5 mL of DCM in the presence ofDMF (2 drops) at 0° C. was added oxalyl chloride (0.1 mL, 0.72 mmol).Then the mixture was stirred at room temperature for an hour, and asolution of Et₃N (0.3 mL) and 3 (80 mg, 0.4 mmol) in 5 mL of DCM wasadded. The resulting mixture was stirred at room temperature for 16hours, and quenched with water (15 mL). The organic phase was separated,and the aqueous phase was extracted with DCM (10 mL×3). The combinedorganic phases were washed with brine (20 mL), dried over anhydrousNa₂SO₄ and filtered. The filtrated was concentrated in vacuo. Theresidue was purified by pre-HPLC (TFA) to give Vismoister as white solid(85 mg, yield: 50.3%). LC-MS m/z: 422.0 [M+H]⁺. LC-MS Purity (214nm): >93%; t_(R)=1.679 min. ¹H NMR (400 MHz, MeOD-d₄): δ 8.75-8.73 (m,1H), 8.31 (d, J=8.0 Hz, 1H), 8.20 (d, J=2.0 Hz, 1H), 8.15 (dt, J=1.6 Hz,J=8.0 Hz, 1H), 8.08 (dd, J=1.6 Hz, J=8.0 Hz, 1H), 7.88-7.85 (m, 1H),7.72 (d, J=8.8 Hz, 1H), 7.66-7.63 (m, 1H), 7.58 (d, J=2.8 Hz, 1H), 7.50(dd, J=2.8 Hz, J=8.8 Hz, 1H), 3.25 (s, 3H).

Example 2: Synthesis of LY-Ester

Synthesis of 3:

A mixture of 1 (533 mg, 5.3 mmol), 2 (1 g, 5.02 mmol) and K₂CO₃ (828 mg,6 mmol) in 10 mL of NMP was stirred at 80° C. for 17 hours. The reactionmixture was diluted with water (50 mL) and extracted withdichloromethane (40 mL×3). The combined organic phases were washed withbrine (50 mL), dried over anhydrous Na₂SO₄, and filtered. The filtratewas concentrated in vacuo. The residue was purified by silica gel column(ethyl acetate:petroleum ether=1:4) to give 3 as white solid (1.2 g,yield: 91.25%). LC-MS m/z: 264.1 [M+H]⁺. LC-MS Purity (214 nm): >94%;t_(R)=1.475 min.

Synthesis of 5:

A mixture of 3 (263 mg, 1.0 mmol), 4 (270.4 mg, 1.3 mmol), Na₂CO₃ (212mg, 2 mmol) and Pd(PPh₃)₄ (57.7 mg, 0.05 mmol) in toluene (10 mL), EtOH(3 mL) and H₂O (3 mL) was stirred at 75° C. for 17 hours. The reactionmixture was cooled to room temperature, diluted with water (40 mL) andextracted with dichloromethane (30 mL×3). The combined organic phaseswere washed with brine (50 mL), dried over anhydrous Na₂SO₄ andfiltered. The filtrate was concentrated in vacuo. The residue waspurified by silica gel column (DCM:MeOH=95:5) to give 5 as red solid(220 mg, yield: 70.1%). LC-MS m/z: 310.2 [M+H]⁺. LC-MS Purity (214nm): >96%; t_(R)=1.255 min.

Synthesis of LY-Ester:

To a stirred solution of 5 (62 mg, 0.2 mmol) and Et₃N (0.1 m1, 0.6 mmol)in 5 mL of dichloromethane was added 6 (68 mg, 0.3 mmol). Then themixture was stirred at room temperature for 17 hours and quenched withwater (10 mL). The organic phase was separated, and the aqueous phasewas extracted with dichloromethane (10 mL×3). The combined organicphases were washed with brine (20 mL), dried over anhydrous Na₂SO₄ andfiltered. The filtrate was concentrated in vacuo. The residue waspurified by silica gel column (ethyl acetate:petroleum ether=1:1) togive LY-ester as white solid (66 mg, yield: 66.1%). LC-MS m/z: 500.1[M+H]⁺. LC-MS Purity (214 nm): >98%; t_(R)=1.726 min. ¹H NMR (400 MHz,CDCl₃): δ 8.14-8.09 (m, 3H), 7.98 (d, J=8.8 Hz, 1H), 7.93-7.84 (m, 2H),7.68 (d, J=2.0 Hz, 1H), 7.57 (d, J=8.4 Hz, 1H), 6.61 (d, J=2.0 Hz, 1H),5.45-5.39 (m, 1H), 4.08 (s, 3H), 3.99-3.93 (m, 2H), 3.64-3.58 (m, 2H),2.38-2.33 (m, 2H), 2.25-2.16 (m, 2H).

Example 3: Synthesis of Erismoester

Synthesis of 3:

A mixture of 2 (579 mg, 3.46 mmol), 1 (500 mg, 2.89 mmol) and K₂CO₃ (1.2mg, 8.7 mmol) in 5 mL of DMF was stirred at 60° C. for 16 hours. Thereaction mixture was diluted with water (50 mL) and extracted with ethylacetate (40 mL×3). The combined organic phases were washed with water(50 mL), brine (50 mL), dried over anhydrous Na₂SO₄ and filtered. Thefiltration was concentrated in vacuo, and the residue was purified bysilica gel chromatography (ethyl acetate:petroleum ether=10:1) to give 3as white solid (650 mg, yield: 85.5%). LC-MS m/z: 266.0 [M+H]⁺. LC-MSPurity (254 nm): >81%; t_(R)=1.964 min.

Synthesis of 5:

A mixture of 3 (500 mg, 1.9 mmol), 4 (262 mg, 2.3 mmol), t-BuOK (851 mg,7.6 mmol), Pd₂(dba)₃ (174 mg, 0.19 mmol) and BINAP (355 mg, 0.57 mmol)in 15 mL of toluene was stirred under N2 protection at 80° C. for 17hours. The mixture was filtered through celite, and the filtrate wasconcentrated in vacuo. The residue was purified by reverse flashchromatography eluted with (NH₄HCO₃/H₂O:CH₃CN=36:64) to give 5 as brownoil (260 mg, yield: 45.9%). LC-MS m/z: 299.7 [M+H]⁺. LC-MS Purity (214nm): >83%; t_(R)=1.998 min.

Synthesis of 6:

A mixture of 5 (250 mg, 0.83 mmol) and 10% Pd/C (15 mg) in 10 mL ofmethanol was stirred under H₂ (1 atm) for 2 hours. The reaction mixturewas filtered through celite, and the filtrate was concentrated in vacuoto give 6 as oil (160 mg, yield: 92.6%).

Synthesis of 9:

A mixture of 7 (228 mg, 1.0 mmol), 8 (288 mg, 1.4 mmol), Na₂CO₃ (212 mg,2 mmol) and Pd(PPh₃)₄(115 mg, 0.10 mmol) in 2 mL of toluene, 2 mL ofethanol and 2 mL of water was stirred under N₂ protection at 80° C. for17 hours concentrated in vacuo. The residue was diluted with ethylacetate (50 mL), washed with water (30 mL) and brine (30 mL), dried overanhydrous Na₂SO₄ and filtered. The filtrate was concentrated in vacuoand the residue was purified by silica gel chromatography (ethylacetate:petroleum ether=1:50) to give 9 as white oil (260 mg, yield:83.8%). LC-MS m/z: 311.1 [M+H]⁺. LC-MS Purity (214 nm): >96%;t_(R)=2.256 min.

Synthesis of 10:

A mixture of 9 (260 mg, 0.84 mmol), LiOH.H₂O (211 mg, 5 mmol) in 3 mL ofTHF, 1 mL of methanol and 1 mL of water was stirred at room temperaturefor 16 hours, and concentrated in vacuo. The residue was diluted withwater (2 mL), acidified with 1M HCl until pH˜3. The suspension wasfiltered to give 10 as white solid (247 mg, 0.99%). LC-MS m/z: 297.1[M+H]⁺. ¹H NMR (400 MHz, CDCl₃): δ 8.06-8.04 (m, 1H), 7.44-7.41 (m, 1H),7.38-7.28 (m, 5H), 2.51 (s, 3H).

Synthesis of Erismoester:

To a mixture of 10 (80 mg, 0.27 mmol) in 3 mL of DCM in the presence ofDMF (1 drop) at 0° C. was added oxalyl chloride (0.04 mL, 0.4 mmol).Then the mixture was stirred at room temperature for 2 hours, and asolution of Et₃N (0.1 m1, 0.8 mmol) and 6 (40 mg, 0.2 mmol) in 5 mL ofDCM was added. The resulting mixture was stirred at room temperature for2.5 hours, diluted with DCM (20 mL) and washed with water (15 mL). Theorganic phase was washed with brine (20 mL), dried over anhydrous Na₂SO₄and filtered. The filtrate was concentrated in vacuo. The residue waspurified by pre-HPLC (TFA) to give Erismoister as brown oil (80 mg,yield: 82%). LC-MS m/z: 487.1 [M+H]⁺. LC-MS Purity (214 nm): >99%;t_(R)=2.374 min. ¹H NMR (400 MHz, CDCl₃): δ 8.14-8.11 (m, 2H), 7.47-7.28(m, 7H), 6.71 (d, J=9.6 Hz, 1H), 4.06-4.02 (m, 2H), 3.79-3.75 (m, 2H),2.60-2.54 (m, 2H), 2.50 (s, 3H), 1.30-1.28 (m, 6H).

Example 4: Biological Assays

Stability Measurements

SMO antagonists were incubated at 250 μM (vismodegib, vismo-ester,erismodegib, erismo-ester) or 25 μM (LY2940680, LY-ester) in human serumor serum-free cell culture media at 37° C. for varying lengths of timeby adding 5 μL of SMO antagonist (10 or 1 mM) to 195 μL of serum ormedia. Reactions were terminated by adding 600 μL of cold acetonitrile.Samples were centrifuged at 1000×g for 15 min at 4° C. and thesupernatant was removed, passed through a 0.22 μm filter, and measuredby LC-MS. The percent remaining of each compound was calculated by theintegrated area of the peak at each time point divided by the peak atthe t=0 time point. Data was fit to a one-phase decay curve usingGraphPad Prism 6 software.

The percent remaining of each compound is shown in FIG. 1 (vismo-esterin comparison with vismodegib), FIG. 2 (erismo-ester in comparison witherismodegib), and FIG. 3 (LY-ester in comparison with LY2940680).

Cell Viability

SmoWT-MB cells are a mouse medulloblastoma cell line with wild-type Smoand Ptch1 loss of function. SmoWT-MB cells were distributed into384-well plates at 1000 cells per well in a total volume of 50 μL andthen pinned with 100 nL of SMO antagonists in quadruplicate over aten-point dose range. Cell viability, relative to DMSO treated cells,was measured after 24, 48, 72, or 96 hours by ATPlite and IC₅₀ wasdetermined by fitting dose-response curves in GraphPad Prism 6 software.

The viability of cells (indicated by the relative luminescenceintensity) is shown in FIG. 4 (24 hour), FIG. 5 (48 hours), FIG. 6 (72hours), and FIG. 7 (96 hours).

Gene Expression Analysis

SmoWT-MB cells were plated at 250,000 cells per well in 6-well tissueculture plates, grown for 24 hours, and treated with 1 μM SMOantagonists or DMSO for 24 hours. After treatment, RNA was extractedfrom cells using the RNeasy kit (Qiagen) and cDNA was prepared from 1 μgRNA using the SuperScript cDNA synthesis kit. The fold-change inexpression for Gli1 and Ptch1, relative to DMSO treatment and normalizedby Hprt, was determined by qRT-PCR using the ΔΔC_(t) method.

The fold change in expression of Gli1 and Ptch 1 is shown in FIGS. 8 and9.

Hh Pathway Cell Reporter Assays

Shh-LightII cells (NIH-3T3 cells stably expressing Gli-dependent fireflyluciferase and constitutively active Renilla luciferase) weredistributed into 24-well tissue culture plates at 150,000 cells per welland grown for 48 hours. Cells were changed to serum-free media and Hhpathway activity was stimulated by 20 nM treatment with Smoothenedagonist (SAG). Cells were treated with 10 μM smoothened antagonist for24 hours (or for 24 hours with an additional dose after 20 hours) andluciferase activity (normalized to Renilla luciferase and relative toDMSO treated cells) was measured using the Dual Luciferase ReporterAssay kit (Promega) as a surrogate for Hh pathway activation.

The reporter expression (indicated by the relative luciferase activity)as modulated by vismo-ester vs. vismodegib, by erismo-ester vs.erismodegib, or by LY-ester vs. LY2940680 is shown in FIG. 10.

The invention claimed is:
 1. A compound having formula II:

or a pharmaceutically acceptable salt thereof, wherein: Z₁-Z₂ is C(O)—O,O—C(O), C(O)—S, S—C(O), C(O)—NR—NR, or NR—NR—C(O); Y₁ is N and Y₂ is Nor CR₂₄; each R₂₄ is independently H, halogen, cyano, unsubstituted orsubstituted C₁-C₆ alkyl, or unsubstituted or substituted C₁-C₆ alkoxy;n2 is 0, 1, 2, 3, 4, or 5; each R₂₁ is independently halogen, cyano,unsubstituted or substituted C₁-C₆ alkyl, unsubstituted or substitutedC₁-C₆ alkoxy, S(O)_(o2)-(unsubstituted or substituted C₁-C₆ alkyl),amino, di-C₁-C₆ alkylamino, or unsubstituted or substituted C₆-C₁₀ aryl;o2 is 0, 1, or 2; m2 is 0, 1, 2, 3, or 4; each R₂₂ is independentlyhalogen, unsubstituted or substituted C₁-C₆ alkyl, or unsubstituted orsubstituted C₁-C₆ alkoxy; R₂₃ is R₂₅, S(O)₂R₂₅, C(O)R₂₅, OR₂₅, orNR₂₆R₂₇; R₂₅ is unsubstituted or substituted C₃-C₈ cycloalkyl,unsubstituted or substituted C₆-C₁₀ aryl, unsubstituted or substitutedheterocyclyl comprising one or two 5- to 8-membered rings and 1-4heteroatoms selected from O, N, and S, or unsubstituted or substitutedheteroaryl comprising one or two 5- to 8-membered rings and 1-4heteroatoms selected from O, N, and S; and R₂₆ and R₂₇ are eachindependently H or unsubstituted or substituted C₁-C₆ alkyl.
 2. Thecompound of claim 1, having formula IIa:

or a pharmaceutically acceptable salt thereof, wherein: Z₃ is O, S, orNR—NR; p2 is 0, 1, 2, 3, or 4; and each R₂₈ is independentlyunsubstituted or substituted C₁-C₆ alkyl.
 3. A pharmaceuticalcomposition comprising the compound of claim 1 or a pharmaceuticallyacceptable salt thereof, and a pharmaceutically acceptable carrier.
 4. Amethod of modulating the SMO, comprising contacting the SMO with thecompound of claim 1 or a pharmaceutically acceptable salt thereof.
 5. Amethod of treating a disorder mediated by the Hedgehog (Hh) signalingpathway, comprising administering to a subject in need thereof, atherapeutically effective amount of the compound of claim 1, or apharmaceutically acceptable salt thereof.
 6. The compound of claim 1,wherein Y₂ is CR₂₄.
 7. The compound of claim 6, wherein R₂₄ is H.
 8. Thecompound of claim 1, wherein n₂ is
 1. 9. The compound of claim 1,wherein R₂₁ is unsubstituted or substituted straight-chain C₁-C₆ alkoxy.10. The compound of claim 9, wherein R₂₁ is trifluoromethoxy.
 11. Thecompound of claim 1, wherein m₂ is
 1. 12. The compound of claim 1,wherein R₂₂ is unsubstituted or substituted straight-chain C₁-C₆ alkyl.13. The compound of claim 12, wherein R₂₂ is methyl.
 14. The compound ofclaim 1, wherein R₂₃ is heterocyclyl optionally substituted with one ormore substituents independently selected from halogen, OH, cyano, nitro,C₁-C₆ alkyl, C₁-C₆ alkoxy, and amino.
 15. The compound of claim 14,wherein R₂₃ is morpholinyl substituted with two substituentsindependently selected from methyl, ethyl, and propyl.
 16. The compoundof claim 1, which is:

or a pharmaceutically acceptable salt thereof, wherein Z is O, S, orNH—NH.
 17. The compound of claim 16, which is:

or a pharmaceutically acceptable salt thereof, wherein Z is O.
 18. Thecompound of claim 1, which is:

or a pharmaceutically acceptable salt thereof, wherein Z is O, S, orNH—NH.